INTR12 XIIth International Symposium on Neural Transplantation and Restoration
Incorporating the 22nd Annual meeting of NECTAR
Cardiff, Wales UK 3rd - 6th September 2013
XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
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INDEX
Welcome 4 Organising Committees 5 Previous International Symposia 7 Our Sponsors 8 Programme 9 Poster Sessions 15 Main Conference Venues 21 Opening Plenary Lecture 22 Conference Centre Plan and Car Parking 23 Conference Facilities 24 Abstracts – Opening Plenary and Oral Presentations 27 Abstracts – Poster Presentations 65 Logo and Travel Awards 106 Conference proceedings 108 Satellite Meeting - Transeuro 109 Hotels and Hotel Map 110 Local Amenities, Shopping and Dining 112 Travel to and from Cardiff 114 Bute Park 115 Things to do in and around Cardiff 116 Meeting Participants 119 Author Index 128 Your Notes 131
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WELCOME A message from the NECTAR President, Emma Lane
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Croeso i Gymru, Welcome to Wales.
It is with great pleasure that I welcome NECTAR members, our colleagues from ASNTR and those from further afield in the INTR community to Cardiff for the XIIth International Symposium on Neural Transplantation and Restoration. The International and Local Programme Committees have done a fabulous job in putting together a great programme which touches on many aspects of CNS transplantation and restoration, bringing us up to date with developments in both basic science and their application to clinic. In addition to the oral prog- ramme we have a series of excellent posters presented in two sessions over Wednesday and Thursday, I hope to meet many of you around these sessions.
The ethos of both NECTAR and INTR communities has always been to promote and support the junior members of the research teams. Thanks to the generous donations from our sponsors, we have been able to offer 20 travel awards to students and post-doctoral fellows from all over the world in a competitive process guided by the International Programme Committee. Congratulations to all the award winners and a big thank you to our sponsors, without whom this conference would not be possible.
That only leaves me to thank the Local Organising Committee for their hard work in coordinating the entire event, in particular the conference organiser Dr Sarah- Jane Richards, and hope you enjoy this conference and sojourn in Cardiff.
COFION CYNNES, WARM REGARD
Emma
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ORGANISING COMMITTEES INTERNATIONAL ADVISORY COMMITTEE (comprising the organisers of previous INTR symposia)
Anders Björklund Stephen Dunnett William Freed Fred H Gage Anne-Charlotte Granholm Marc Peschanski Paul Sanberg Shinn-Zong Lin Guido Nikkhah John Sladek Jens Zimmer
LOCAL ORGANISING COMMITTEE
Emma Lane (chair) – [email protected] Stephen Dunnett – [email protected] Anne Rosser – [email protected] Sarah-Jane Richards (meeting organiser) – [email protected] Vanessa Davies (secretariat) – [email protected] Catherine Hortop (secretariat) – [email protected]
Address: INTR12, The Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK Tel: +44 (0)2920 875188 Fax: +44 (0)2920 876749 Bank: Lloyds TSB, Cardiff Business Branch – sort code 30-67-64 account name: INTR12 – account number: 12115168 BIC LOYDGB21707 – IBAN GB77 LOYD 3067 6412 1151 68
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OFFICERS NECTAR BOARD
Emma Lane (President) Roger Barker Angela Cenci-Nilsson Maté Döbrössy Eilís Dowd Paola Piccini Christian Winkler
ASNTR BOARD
Ted Teng (President) Sandra Acosta (Student) Kimberly Bjugstad Marcel Daadi Gary Dunbar Marina Emborg Howard Federoff Svitlana Garbuzova-Davis Carmelina Gemma Mike Modo Alison Willing David Yurek
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PREVIOUS (& FORTHCOMING) INTERNATIONAL INTR SYMPOSIA
dates venue host
INTR1 1984 Lund, Sweden Anders Björklund INTR2 1986 Rochester NY, USA John Sladek INTR3 1989 Cambridge UK Stephen Dunnett INTR4 1992 Washington DC, USA William Freed INTR5 1994 Paris, France Marc Peschanski INTR6 1997 San Diego CA, USA Fred H Gage INTR7 1999 Odense, Denmark Jens Zimmer INTR8 2002 Keystone CO, USA Lotta Granholm INTR9 2005 Taipei, Taiwan Shinn-Zong Lin INTR10 2008 Freiburg, Germany Guido Nikkhah INTR11 2010 Clearwater Beach FL, USA Paul Sanberg INTR12 2013 Cardiff, Wales, UK Emma Lane INTR13 2015 Beijing, China Wei-Ming Duan
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INTR12 SPONSORS We greatly thank our sponsors for their generous support:
C.A.R.E. the Campaign for Alzheimer’s Research www.alzheimerscare-eu.org/ in Europe
GE Healthcare www3.gehealthcare.co.uk/
Parkinson’s UK www.parkinsons.org.uk/
Movement Disorder www.movementdisorders.org/ Society
Cardiff University www.cardiff.ac.uk/
Neuroscience and Mental www.cf.ac.uk/research/neuroscience/ Health Research Institute
Company of Biologists www.biologists.com/
NeuroDem Cymru www.neurodemcymru.org
Olympus www.olympus.co.uk
Sandown Scientific www.sandownsci.com/
Lundbeck www.lundbeck.com/uk/
Campden Instruments www.campden-inst.com/
Action for the Victims of A.V.O.D.A. Contact C.A.R.E. Dopamine Agonists
Lloyds TSB Bank www.lloydstsb.com/
NeuroReport journals.lww.com/neuroreport/
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2013 INTR12 PROGRAMME Day 1 – Tuesday September 3rd – Public lecture
(sponsored by the Neuroscience & Mental Health Research Institute)
Venue (reception): Welsh National Museum (lecture): Reardon Smith Lecture theatre NB. Admittance strictly by ticket only
Time Speaker Title
17.30 Wine and canapé reception
Public Lecture 18.40 Emma Lane Welcome, Introduction to INTR12 Symposium host 18.45 Prof Sir Martin Evans Introduction of speaker and stem cell Nobel Prize winner for context Physiology or Medicine 2007 19.00 Prof Sir John Gurdon The origins and future of pluripotency and Nobel Prize winner for cellular reprogramming Physiology or Medicine 2012 20.00 Mike Owen Vote of thanks Director, NMHRI
Finish
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Day 2 - Wednesday, 4th September 2013. Morning Venue: Hilton Hotel Ballroom Time Speaker Title 8.45 Emma Lane Welcome to INTR12 Session 1 Cell and Gene therapy for Parkinson’s disease 1 Chairs: Anders Björklund, Meng Li 9:00 Yves-Alain Barde Neurotrophins : from bench to bedside (Cardiff, UK) 9:40 Stephen Gill GDNF – back in the clinic (Bristol, UK) 10:20 Roger Barker Transeuro clinical trials update (Cambridge, UK) 10:35 Zinovia Kefalopoulou Very long-term clinical outcome of fetal (London, UK) striatal transplantation for PD 10:50 Coffee Break & Poster Session 1 Session 2 Cell and Gene therapy for Parkinson’s disease 2 Chairs: Lachlan Thompson, Roger Barker 11:15 Stéphane Palfi Prosavin, a dopamine gene therapy for (Paris, France) advanced PD: phase I clinical update 11:55 Hideki Mochizuki Gene therapies for hereditary PD; a strategic (Osaka, Japan) transition from in vivo to ex vivo 12:10 Wei-Ming Duan AAV9-mediated EPO gene delivery in a rat (Beijing, China) model of PD 12:25 Mariah Lelos Human ventral mesencephalic grafts alleviate (Cardiff, UK) both motor and non-motor dysfunctions in a rodent model of PD 12:40 Daniella Rylander Region-specific restoration of striatal synaptic (Lund, Sweden) plasticity by dopamine grafts in experimental parkinsonism 12:55 Lunch 14:00 Poster Session 1 Presenters to attend their posters
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Day 2 - Wednesday, 4th September 2013. Afternoon Venue: Hilton Hotel Ballroom
Time Speaker Title Session 3 Sources of fate specific cells Chairs: Malin Parmar, Philippe Hantraye 14:30 Malin Parmar Generating neurons for use in cell therapy; (Lund, Sweden) challenges and possibilities 15:10 Luis Azmitia Directly reprogrammed neural precursors (Freiburg, Germany) from patient-specific fibroblasts 15:25 Federica Rinaldi Differentiation of human pluripotent stem (Bristol, UK) cells into brain-regionalized astrocytes to investigate pathogenesis of Parkinson’s and Alzheimer’s diseases 15:40 Meng Li Directing striatal GABAergic fate specification (Cardiff, UK) of human pluripotent stem cells
15:55 Coffee Break and Poster Session 1
Session 4 Cell and gene therapy of striatal degeneration Chairs: Anne Rosser, Meng Li 16:20 Sarah Tabrizi TRACK-HD and TRACK-ON HD – yielding new (London, UK) insights into Huntington’s disease 17:00 Gaynor Smith Rab1A and Rab3B gene therapy in the Q175 (Belmont MA, USA) knock in model of Huntington’s disease 17:15 Jordan Wright Production of new striatal neurons in the (Melbourne, Australia) healthy and diseased neonatal brain Special Lecture. Chair: Wei-Ming Duan 17:30 Arturo Alvarez-Buylla Repairing neural circuits with local circuit (USA) neurons
18:30 End of session. Free evening
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Day 3 - Thursday 5th September 2013. Morning Venue: Hilton Hotel Ballroom Time Speaker Title
Session 5 Guidance of axon growth and connectivity Chairs: Clare Parish, Eilis Dowd 09:00 James Fawcett Targeting the extracellular matrix for CNS (Cambridge) repair 09:40 Siddharthan Chandran Cellular autonomy and neurodegeneration (Edinburgh, UK) 10:20 Ben Newland Encapsulation of stem cells in an in situ (Galway, Ireland) gelling collagen hydrogel improves graft volume and striatal retention after intra- cerebral transplantation in the rat
10:35 Coffee Break and Poster Session 2
Session 6 Imaging and spinal cord Chairs: Cesar Borlongan, Liam Gray 11:00 Philippe Hantraye Imaging stem cell fate following (Orsay, France) intracerebral grafting 11:40 Hongyun Huang Global clinical neurorestoration in complete (Beijing, China) chronic spinal cord injury 11:55 Genevieve Gowing Generation of human neural progenitor cells (Los Angeles, USA) from induced pluripotent stem cells that survive, migrate and integrate into the rodent spinal cord 12:10 Brandon Shelley Clinical-grade neural progenitor cells (Los Angeles, USA) secreting GDNF for the treatment of ALS
12:25 Lunch 13:30 Poster Session 2 Presenters to attend their posters
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Day 3 - Thursday, 5th September 2013. Afternoon Venue: Hilton Hotel Ballroom
Time Speaker Title
Session 7 Restorative strategies for neurodegeneration Chairs: Jens Zimmer, Siddharthan Chandran 14:00 Catherine Verfaillie Adult stem cell-based therapy for ischemic (Leuven, Belgium) stroke 14:40 Cesar Borlongan Stem cell therapy for stroke: preclinical (Tampa FL, USA) evidence and an update on FDA-approved clinical trials 15:20 Manuela Gernert Grafting of rat and porcine fetal neuronal cells (Hannover, Germany) into the subthalamic nucleus in experimental epilepsy 15:35 William Gray Modulating endogenous stem cells to restore (Cardiff, UK) learning and memory in Temporal Lobe Epilepsy 15:50 Emma Kidd Anti-amyloid precursor protein antibodies as a (Cardiff, UK) potential therapy for Alzheimer’s disease 16:05 Coffee Break & Poster Session 2
Special Lecture. Chair: John Sladek 16:30 Mark Tuszynski Growth factor gene therapy for Alzheimer's (La Jolla CA, USA) disease: NGF and BDNF 10 min break 17:40 INTR Business meetings Wei-Ming Duan INTR13 – Beijing in 2015 Lachlan Thompson INTR14 – Proposal(s) for 2017/18 18:00 NECTAR Business meeting Eilís Dowd NECTAR – Proposal for 2014 19:30 for 20:00 Gala Dinner Venue: Park Plaza Hotel – opposite Hilton, 50 yards to the right. Sponsor: The Gala dinner is generously sponsored by GE Healthcare Dress code: smart casual. Entrance: by conference badge only.
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Day 4 – Friday 6th September 2013. Morning Venue: Hilton Hotel Ballroom
Time Speaker Title
Session 9 Guidance of stem cells Chairs: James Fawcett, Stephen Dunnett 9:00 Pierre From pluripotent stem cells to cortical circuits: Vanderhaeghen perspectives for disease modelling and brain (Brussels, Belgium) repair 9:40 Conor Ramsden Experimental and clinical transplantation of (London, UK) pluripotent stem cells for cell therapy in retinal disease 10:20 Christelle Monville Clinical application of retinal pigment (Évry, France) epithelium (RPE) cells derived from human embryonic stem cells 10:35 Evan Snyder Midkine (MDK): a newly-recognized (La Jolla CA, USA) endogenously-produced cytokine that, through an autocrine mechanism, is pivotal for neural induction
10:50 Coffee Break
Special lecture. Chair: Evan Snyder 11:15 John Sladek From Thompson to Hopkins-Dunn to Ranson; if (Denver CO, USA) the Pioneers could see us now! 12:15 Emma Lane Closing remarks and Farewell Wei-Ming Duan
12:55 Lunch
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POSTER SESSION 1 9am – 6pm, Wednesday 4th September 2013. Posters are listed by poster board number in the Conference Centre atrium. Numbers in square brackets refer to the poster abstracts, arranged alphabetically on pages 65-105. Poster presenters: please mount your posters between 8am and 9am before the first oral session of the morning. Presenters should be present at their posters for the 30 min poster session at 13:30 after the lunch break. Posters to be taken down between 6pm and 7pm after the last session of the afternoon.
Parkinson’s disease 1. A potential compensatory role for endogenous striatal tyrosine hydroxylase- positive neurons in a non-human primate model of Parkinson’s disease [P3]. Bubak AN, Redmond DE Jr, Elsworth JD, Roth RH, Collier TJ, Bjugstad KB, Blanchard BC and Sladek JR (Colorado-Denver, Yale and Michigan State, USA). 2. Birth dating of dopamine neuron subtypes in ventral mesencephalon grafts in a rat model of Parkinson’s disease [P7]. Fjodorova M, Torres EM and Dunnett SB (Cardiff, UK). 3. Sedimentation of cell suspensions in large diameter cannulae: is it a problem? [P37]. Trigano M, Torres EM and Dunnett SB (Paris, France & Cardiff, UK). 4. The influence of nicotinamide on directed differentiation of neurons from embryonic stem cells in vitro [P11]. Griffin SM, Pickard MR, Orme RP, Hawkins CP and Fricker RA (Keele, UK). 5. Influence of transcranial direct current stimulation on the survival, migration and integration of dopaminergic cell transplants in a rat model of Parkinson´s disease: a histological and behavioral analysis [P16]. Fritsch B, Hoffmann N, Furlanetti L, García J, Döbrössy MD and Winkler C (Freiburg, Germany).
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6. Trefoil Factor 1 in the nigrostriatal system of 6-hydroxydopamine-lesioned rats [P17]. Jensen P, Heimberg M, Ducray AD, Widmer HR and Meyer M. (Odense, Denmark and Bern, Switzerland). 7. Antagonizing Nogo-receptor 1 promotes the number of cultured dopaminergic neurons and elongates their neurite [P29]. Seiler S, Pollini D, Di Santo S and Widmer HR (Bern, Switzerland). 8. Differential neuroprotective capacity of endothelial progenitor cells-derived factors [P5]. Di Santo S, Seiler S and Widmer HR (Berne, Switzerland). 9. Transplantation of fetal ventral mesencephalic progenitor cells overexpressing high molecular weight FGF-2 isoforms in 6-OHDA lesioned rats [P28]. Rumpel R, Klein A, Ratzka A, Özer M, Wesemann M and Grothe C (Hannover, Germany). 10. EGFP-Flag transfected rat progenitor cells display electrophysiological properties of integrated functional dopaminergic (DA) neurons similar to genetically labelled DA-neurons in vitro and intrastriatally xenografted DA- neurons in a rat model of Parkinson’s disease [P23]. Özer M, Rumpel R, Fischer M, Donert M, Klein A, Wesemann M, Ratzka A, Effenberg A, Fahlke C and Grothe C (Hannover and Jülich, Germany). 11. The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation [P30]. Shin E, Lisci C, Tronci E, Fidalgo C, Stancampiano R, Björklund A and Carta M (Lund, Sweden and Monserrato, Italy). 12. Optogenetic manipulation of hESCs and in vivo measurement of dopamine release [P15]. Heuer A, Grealish S, Kirkeby A, Lundblad M and Parmar M (Lund, Sweden). 13. Generating patient-derived Parkinsonian iPS cell lines, their differentiation to midbrain dopaminergic neurons and susceptibility to neurotoxic insults [P1]. Barbuti PA, Badger JL, Crompton LA, Whone AL, Uney JB and Caldwell MA (Bristol, UK).
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14. AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in parkinsonian rat and mouse model [P41]. Zhang T, Ren XM, Gong X, Hu G, Ding W and Wang W (Beijing, China). 15. Understanding rejection of allogeneic and xenogeneic dopaminergic cell transplants [P2]. Breger LS, Dunnett SB and Lane EL (Cardiff, UK). 16. Vitamin D3 promotes dopamine neuron survival through upregulation of GDNF [P8]. Orme RP, Bhangal M and Fricker RA (Keele, UK). 17. Cell intrinsic and extrinsic factors contribute to enhance neural circuit reconstruction following transplantation in Parkinsonian mice [P19]. Kauhausen J,, Thompson L and Parish C (Melbourne, Australia). 18. Human fetal dopaminergic precursor cell transplantation: LIF-nanotherapy to promote graft survival [P21]. Metcalfe SM, Zhao JW, Tyers P, He X, Fahmy TM and Barker RA (Cambridge UK and Yale, USA). 19. Neonatal immune-tolerance in mice does not prevent xenograft rejection; a comprehensive analysis using in vivo luciferase tracking [P20]. Mattis VB, Wakeman DR, Tom C, Dodiya HB, Reidling J, Tran A, Bernau K, Ornelas L, Sahabian A, Sareen D, Thompson LM, Kordower JH and Svendsen CN (Los Angeles, Chicago, Irvine and Madison, USA). 20. Influx of blood monocytes to the brain is enhanced by antioxidants [P32]. Rehnmark A, Lopes P, Faegermann E, Orädd G, Virel A and Strömberg I (Umeå, Sweden). 21. Identification of novel brain endogenous Liver X Receptor ligands that selectively promote red nucleus or midbrain dopamine neurogenesis [P12]. Theofilopoulos S, Wang Y, Griffiths W and Arenas E (Stockholm, Sweden). 22. Characterizing GDNF regulation and its impact in the of 6-OHDA rodent model [P25]. Quintino L, Elgstrand-Wettergren E, Manfré G, Isaksson C and Lundberg C (Lund, Sweden).
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POSTER SESSION 2 9am – 6pm, Thursday 5th September 2013. Posters are listed by poster board number in the Conference Centre atrium. Numbers in square brackets refer to the poster abstracts, arranged alphabetically on pages 65-105. Poster presenters: please mount your posters between 8am and 9am before the first oral session of the morning. Presenters should be present at their posters for the 30 min poster session at 13:30 after the lunch break. Posters to be taken down between 6pm and 7pm after the last session of the afternoon.
Huntington’s Disease and Striatal Repair 23. The development of operant delayed matching to position for Huntington’s disease mouse models [P40]. Yhnell E, Dunnett SB and Brooks SP (Cardiff, UK). 24. Are transplant-induced improvements in cognitive performance in the rat lesion model of Huntington’s disease dependent on frontal-striatal circuit reconnection? [P14]. Harrison DJ, Brooks SP and Dunnett SB (Cardiff, UK). 25. Comparison of mouse and human developing striatal gene expression [P38]. Vinh NN, Kelly, CM, Heuer A, Precious SV, Allen ND, Kemp PJ and Rosser AE (Cardiff, UK). 26. Direct programming of neural stem cells into medium spiny neurones by transcription factor transfection [P9]. Geater CR, Kemp PJ and Allen ND (Cardiff, UK). 27. Human Induced Pluripotent Stem (iPS) Cells for Cell Replacement Therapy in Huntington's disease [P4]. Choompoo N, Vinh NN, Kelly CM and Rosser AE (Cardiff, UK). 28. Characterisation of FoxP1 in the striatum [P6]. Evans AE, Taylor MV and Rosser AE (Cardiff, UK).
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29. Comparison of L-Dopa response patterns of different stages of MSA-P in a double lesion rat model [P18]. Kaindlstorfer C, García J, Stefanova N, Poewe W, Winkler C, Döbrössy M and Wenning G (Innsbruck, Austria and Freiburg, Germany).
Repair Strategies in Other CNS disorders 30. Proof-of-concept: The use of human induced pluripotent stem cells (hiPSCs) to uncover a novel developmentally-based target of therapeutic lithium in bipolar disease (BPD) [P31]. Tobe BTD, Crain AM, Winquist AM, Sidor M, Calabrese B, Brandel M, Duerr C, McCarthy M, McClung C, Halpain S, Singec I and Snyder EY (La Jolla and Pittsburgh, USA). 31. Safety study on cyclosporine A in epilepsy models [P13]. Handreck A, Mall EM, Elger DA, Gey L and Gernert M (Hannover, Germany). 32. A microRNA profile of reduced mir-34b/c and increased mir-592 in adult epileptic patient-derived brain cells reveals potent disease biomarker and screening tool for transplantable stem cells [P33]. Tajiri N, Ishikawa H, Shinozuka K, Dailey T, Sullivan R, Kaneko Y, Malapira T, Gemma C, Vale F and Borlongan CV (Tampa, USA). 33. Histopathological effects of varying the impact trajectories in experimental model of TBI [P24]. Pabón MM, Tajiri N, Shinozuka K, Acosta S, Ishikawa H, Hernandez-Ontiveroz D, Vasconcellos J, Dailey T, Metcalf C, Staples M, Tamboli C, Kaneko Y and Borlongan CV (Tampa, USA). 34. Generation of cortical interneuron subtypes from human pluripotent stem cells [P34]. Tamburini C, Arber C and Li M (Cardiff, UK). 35. Caveolin-1 alters the amyloidogenic processing of amyloid precursor protein to amyloid-beta [P36]. Thomas RS and Kidd EJ (Cardiff, UK). 36. Recovery neurobiology of spinal cord injury: mechanisms gleaned from peripheral neurotization studies [P35]. Teng YD, Konya D, Yu D, Anderson J and Zeng X (Boston, USA).
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37. Vascularization for neural repair and stem cell transplantation by hyaluronan-peptide hydrogels [P39]. Wang Y, Ju R, Wen SLY, Yu S and Xu Q (Beijing, China). 38. Controlled release of neurotransmitters from biopolymer matrices influence neural stem cell proliferation and distribution [P27]. Romanyuk N, Vetrik M, Karová K, Jendelová P, Hruby M, Price J and Syková E (Czech Republic). 39. Desensitisation of rat hosts to neural xenografts without conventional immune suppression [P26]. Roberton VH, Kelly CM and Rosser AE (Cardiff, UK). 40. Simultaneous in vivo monitoring of transplanted cells and biomaterials by magnetic resonance imaging [P22]. Modo M (Pittsburgh, USA). 41. Effective transplantation of photoreceptors derived from three-dimensional cultures of embryonic stem cells [P10]. Gonzalez-Cordero A, West E, Pearson R, Sowden J and Ali RR (London UK).
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MAIN CONFERENCE VENUE
Hilton Hotel Cardiff The Hilton Hotel is the main conference venue. Based in the heart of the city, the Hilton is situated directly opposite Cardiff Castle, Bute Park and the National Museum of Wales; it, is close to all facilities and amenities of central Cardiff and is only 10 minute walk from Cardiff Central Railway station.
INTRODUCTORY OPEN LECTURE The National Museum of Wales The opening reception is located in the galleries of the National Museum of Wales, directly opposite the Hilton Hotel via the pedestrian underpass. The ‘Nobel-themed’ opening plenary lecture follows the reception to be held in the Reardon Smith lecture theatre, part of the National Museum buildings with a separate entrance in Park Place.
GALA DINNER Park Plaza Hotel The Gala dinner on Thursday night is spon- sored by GE Healthcare. The dinner will be held in the Park Plaza hotel, located 50 yards from the Hilton on the other side of the street to the right (as you exit the front entrance). Drinks from 7:30 for dining at 8pm. Dress: smart casual.
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OPENING PLENARY LECTURE The INTR12 Local Organising Committee are pleased to announce the acceptance by Professor John Gurdon (Nobel Prize in Physiology or Medicine, 2012) to present the opening plenary lecture of the XIIth International Symposium on Neural Transplantation and Restoration. The lecture is hosted jointly with the Cardiff University Neuroscience and Mental Health Research Institute. Opening Reception (from 17:30). The National Museum of Wales galleries. Plenary Lecture (18:40 – 20:00). Reardon Smith Lecture theatre, Cardiff Guests are requested to take their seats by 6:30pm Welcome Dr. Emma Lane (Welsh School of Pharmacy, NECTAR President & INTR12 Chair) Introduction of speaker Prof. Sir Martin Evans (Chancellor, Cardiff University, Nobel laureate 2007) Plenary Lecture: Prof. Sir John Gurdon (Cambridge University, Nobel laureate 2012) The origins and future of Pluripotentiality and cellular reprogramming Vote of Thanks Prof. Mike Owen (Director, Neuroscience and Mental Health Research Institute) Professor Sir John Gurdon Professor Sir John Gurdon is a Distinguished Group Leader in the Wellcome Trust / CRUK Gurdon Institute at Cambridge University. The Nobel Prize in Physiology or Medicine 2012 was awarded jointly to John Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogram- med to become pluripotent"
Tickets: Admission is strictly by ticket only. Tickets will be allocated first to registered attendees of the INTR12 meeting, members of the Cardiff University NMHRI and neuroscience community, and invited guests.
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CONFERENCE CENTRE PLAN
Car Parking Car parking is available at the Hilton at a cost of £10 daytime (£20 overnight). Leave car at front door for valet parking. The National Car Parks multi-story car parking in Greyfriars Road CF10 3AD is only 100 yards from the Hilton, and charges £18 for 4-24 hours. Free off-street parking can be found in the backstreets beyond Cathays station, but it can be difficult to find spaces during daytime (enquire at Conference desk).
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CONFERENCE FACILITIES Conference Desk The Conference and registration Desk will open from 8am on each morning Wednesday 4th, Thursday 5th and Friday 6th September, and will be manned by Sarah-Jane, Vanessa and Cath and their helpers throughout the symposium. Registration Your registration badge, opening reception and Gala dinner tickets should be collected with your conference bag on registration at the Conference Desk. Conference registration will also be available at the Welcome Reception at the National Museum of Wales on Tuesday evening from 5:15 - 6:30pm. Help and Advice Please address all queries, requests and problems to the team on the Conference Desk and we will do our very best to assist. Auditorium Please wear your conference badge at all times. Entrance to the auditorium will be monitored. Please note that the proceedings are to be recorded. Oral Presentations Genero is operating the audio-visual projection amplification and recording systems. Presentations should be prepared to operate in PowerPoint, and must be stored on a memory stick for loading onto the projection system. Please present your memory stick to the AV desk at the front of the auditorium, before the start of the morning session for all morning presentations, and during the lunch break for all afternoon presentations. If you can provide your presentation in advance please do so; we will store it in your allocated session. The AV staff will upload and check each presentation and have facilities for you to review all is correct. We apologise that we cannot accommodate switching between personal laptops during the oral sessions, so please allow good time to upload if you have a complex multi-file presentation.
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Microphones Roving microphone amplification will be available, both for the speakers, and for the audience during question and discussion periods. Poster Boards Poster sessions. There are two poster sessions, thematically organised, all day on Wednesday 4th and on Thursday 5th September. The poster boards are located close by the auditorium, and available for viewing in extended tea, coffee and lunch breaks. Poster mounting. Please mount your posters 8:00 - 8:45am before the morning session, and remove 6:00 - 7:00pm after the end of the afternoon session on the day on which your poster is scheduled. Each poster is allocated a poster board number, as detailed on pages 15ff of this booklet. Posters are to be attached by Velcro dots, which will be provided. A team of helpers is available to assist in locating the correct board, providing Velcro dots, and any other assistance you may seek. Poster preparation. The boards are mounted in portrait mode, 100cm wide x 160cm high, and readily accommodate international A0 format printed posters. Poster presenters should be present at their posters for the 30 min session immediately following the lunch break. Teas and Coffees Tea, coffee and soft drinks are served by the hotel to all registered participants during scheduled coffee and lunch breaks. Please wear your conference badges. At other times the Hilton bar and café are available close by for purchase of a wider range of drinks and snacks. Lunch Buffet lunch will be served by the hotel to all registered participants at the scheduled times following the end of each morning session. Please wear your conference badges. For any special dietary needs, please speak to the conference desk.
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CPD Attendance at the INTR12 symposium is in the process of accreditation with the Royal College of Physicians (London) for award of Continuing Professional Development credits. For certificates please enquire at the Conference desk at any time on the first full day (Wednesday 4th September) of the meeting. WiFi facilities We have negotiated a 50% discount (£7.50) on the hotel daily rate for wireless internet access. Please purchase login codes at the hotel reception desk. Social media We will be tweeting live throughout the conference @NECTAR_eu. Please do comment and tag your tweets with #INTR12. Tweets are posted live to our website and Facebook page. Alternatively, visit our Facebook page directly and find us at Nectar Pres (https:// www.facebook.com/nectar.pres?fref=ts). For any private discussion request to join the closed NECTAR group (https:// www.facebook.com/groups/275578479149617/?fref=ts). The Gurdon lecture will be video recorded and will be available to view on the NMHRI website (http://www.cardiff.ac.uk/research/neuroscience/news/). The programme and abstracts will remain available online at www.nectar-eu.net. Commercial displays Olympus is presenting a commercial display stand in the area in the Atrium. The company is sponsoring our meeting and have allowed us to award more travel awards. Please credit them by showing interest in the stands. First Aid The hotel has its own first aid medical service, via the hotel concierge desk. Alternatively please speak to our team on the Conference Desk.
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ABSTRACTS – OPENING PLENARY LECTURE O1. Gurdon The origins and future of pluripotency and cellular reprogramming Professor Sir John Gurdon The Gurdon Centre, University of Cambridge, Tennis Court Road, Cambridge, UK. (Email: [email protected]). The different cell types that compose our bodies are remarkably stable. Hardly ever do we find skin cells in the brain or liver cells in the heart. In those very special cases where some regeneration can take place in vertebrates, there is little if any evidence for a switch in cell-type. Nevertheless, nuclear transfer, cell fusion, and induced pluripotency can result in pluripotent embryo cells being derived from specialized adult cells. The mechanisms by which nuclear reprogramming can occur in these cases is beginning to be understood. It may become possible for new, regenerated cell-types to be derived from adult cells and given back to a patient so that they receive new cells of their own genetic constitution, thereby avoiding the need for immunosuppression. The history of work in this area, and the prospects for cell replacement in the future will be discussed.
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ABSTRACTS – ORAL PRESENTATIONS O2. Alvarez-Buylla Repairing Neural Circuits with Local Circuit Neurons Arturo Alvarez-Buylla Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, 35 Medical Center Way, San Francisco, CA 94143-0525, USA. (Email: [email protected]). Cortical GABAergic interneurons originate in the subpalial ganglionic eminences (GE). Their integration into the forebrain and cortical circuits is essential to achieve proper inhibitory- excitatory balance and appears to also be key for the induction of cortical plasticity. Importantly, these cells retain their long-range migratory potential and can integrate into neural circuits when grafted into the postnatal and adult brain. Remarkably, their numbers are not adjusted by exogenous signals, but internally in a cell or population autonomous manner. This allows for the addition by transplantation of numerous interneurons to cortex that disperse and functionally integrate. These grafted cells can reinitiate periods of cortical plasticity and can repair imbalances in animal models of epilepsy. Cortical interneuron transplantation is likely to have a wider therapeutic use as we learn more about how specific subtypes of these GABAergic cells are affected in different human diseases. I will discuss recent data suggesting the large-scale contribution of caudal and probably lateral GEs to the human cortical interneuron population. Interestingly, some of these large streams of putative migrating interneurons are retained into the postnatal human brain. These findings suggest new approaches for the repair of cortical circuits.
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03. Azmitia Directly Reprogrammed Neural Precursors From Patient-Specific Fibroblasts Luis Azmitia 1, Philipp Capetian 2, Mariana Klett 1, Máté Döbrössy 1 and Guido Nikkhah 3 1 Stereotactic and Interventional Neuroscience Laboratory, University Hospital Freiburg, Germany. 2 Section of Clinical and Molecular Neurogenetics, University Hospital Lübeck, Germany. 3 Department of Neurosurgery, University Hospital Erlangen, Germany. (Email: [email protected]). Yamanaka et. al. 2007, appeared as a mile stone in cell reprogramming exploring a source of induced pluripotent stem (iPS) cells, a valuable tool and ally for cell therapy. Nevertheless, the process continued to be complicated and time consumption, involving risks of vector integrations. We combined an insertion free approach of transfecting 3 plasmids carrying the reprogramming factors (Okita et. al., 2011) into fibroblasts from Huntington's disease (HD) patients. The cells were propagated under neuralizing conditions and neural rosettes (2 weeks after transfection) were allowed to get confluent, picked and expanded; leading to a high yield of directly reprogrammed neural cells (drNCs). drNCs were positive for Nestin, BIII Tubulin, PLZF and ZO1; and evidenced Neurotensin, FoxG1, LHX9 and Pax6. Thereafter the exposure to FGF2, FGF8, Purmorphine and CHIR99020; DLX, DSH, OTX2, GAD67 and Darpp32 were confirmed. 21 weeks after transplantation, Nestin, BIII, PSA-NCAM, GFAP, Oligodendrocyte2 and Glutamate were positive with no signs of tumor formation. This model, gave rise an early developmental phenotype of stem cells (forebrain). It evidenced malleability through addition of growth factors and small molecules: rostralization of an established commitment, including Darpp32 positive cells. It highlights a valuable tool in understanding the neurodegenerative diseases and neural development.
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O4. Barde Neurotrophins: from bench to bedside Yves-Alain Barde School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK (Email: [email protected]). Neurotrophins are small dimeric proteins encoded by 4 genes in mouse and human. The lack of such genes in species used by geneticists to dissect signaling pathways has seriously complicated progress in this field. Thus, only recently was it realized that 2 of the long known neurotophin tyrosine kinase receptors, TrkA and TrkC actually kill neurons in the absence of ligand-mediated activation, thus explaining the dependency for survival of some neurons on nerve growth factor established over 50 years ago 1. In addition, the strong structural relatedness of neurotrophins and their receptors led to unwarranted extrapolations about their mode of action. In particular, nerve growth factor in the peripheral nervous system served as the dominant conceptual framework to infer how neurotrophins would work in the brain. But recent results indicate that brain-derived neurotrophic factor (BDNF), by far the most widespread neurotrophin in the brain, is localized pre- and not post-synaptically in the nerve terminals of excitatory neurons2 and that it is not a significant survival factor for most CNS neurons 3. This is in line with functional results obtained by others indicating that the rodent striatum is fed forward by cortical afferents delivering BDNF, a significant body of work of high relevance to diseases such as Huntington’s. This feed forward mechanism seems to be needed by many GABA- ergic neurons to reach, possibly also to keep, their normal size even if BDNF is not needed for their survival. For example, in animals lacking Mecp2, the gene associated with most cases of Rett Syndrome, the levels of BDNF are markedly reduced in some brain areas, including the cerebral cortex. In young adult animals, the size of the striatum is significantly decreased in Mecp2 mutants4 and we recently showed that the sphingosine analogue fingolimod, a drug recently introduced as the first oral treatment of multiple sclerosis, increases BDNF levels and restores the size of the striatum to a volume close to normal4. It is possible then that BDNF levels may modulate the growth of some brain areas even in the adult, a notion that has hardly been explored thus far, in large part because of misleading results obtained with transgenic animals overexpressing BDNF. However, recent results from our laboratory indicate that BDNF overexpression leads to the secretion of unprocessed pro-BDNF, a protein counteracting the growth effects mediated by processed BDNF. By contrast, results obtained with another mouse mutant indicate that increased levels of physiologically processed BDNF are accompanied by a progressive, massive growth of some brain areas in the adult 2,5. These new results suggest then that while BDNF is not a significant factor for the survival of most CNS neurons, in line with finding that its receptor TrkB does not cause neuronal death in the absence of ligand1, it may regulate the size of various brain areas, even in the adult.
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References 1 Nikoletopoulou et al. (2010) Neurotrophin receptors TrkA and TrkC cause neuronal death while TrkB does not. Nature 467, 59-63. 2 Dieni et al. (2012) BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons. J. Cell Biol. 196, 775-788. 3 Rauskolb S. et al. (2010) Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth J. Neurosci. 30, 1739-1749. 4 Deogracias (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 109, 14230-14235. 5 Heyden et al. (2011) Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels. Cell Tissue Res. 346, 11-26
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O5. Barker TRANSEURO: what has it achieved to date? Roger A. Barker, on behalf of the TRANSEURO consortium. Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB1 6JY. (Email: [email protected]). Trials of human fetal ventral mesencephalic tissue (hfVM) transplants in patients with Parkinson's Disease (PD) have produced mixed results with some individuals showing excellent long term outcomes and others developing side-effects without benefit. The reasons for this may relate to patient selection, tissue preparation and support (pre and post implantation) and trial design. In 2006 a working group was set up to discuss these issues which led to the successful funding of an EU-FP7 grant looking at hfVM grafts in a new trial, called TRANSEURO. Over the last 3-4 years TRANSEURO has moved to the point of starting this new trial by addressing issues in the laboratory to do with tissue preparation at a GMP level, as well as recruiting and following up a cohort of younger early stage patients using clinical and imaging assessments. In this talk I will outline the rationale and status of this new trial.
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O6. Borlongan Stem cell therapy for stroke: Preclinical evidence and an update on FDA- approved clinical trials Cesar V Borlongan Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612 USA. (Email: [email protected]). BACKGROUND AND PURPOSE: Stem cells possess excellent therapeutic applications for ischemic brain injury. In this talk, I will provide scientific evidence that intravascular and intracerebral transplantation of stem cells produce behavioral and histological benefits in experimental models of stroke. I will highlight gating preclinical evidence that form the basis for translating stem cell therapy in stroke from the laboratory to the clinic. METHODS: In carefully assessing the safety and efficacy of stem cell therapy for stroke, I refer to the 3 meetings of STEPS or Stem cell Therapeutics as an Emerging Paradigm for Stroke. Here, I will discuss the lab-to-clinic experimental design that is of keen interest to the academicians, physicians, NIH program directors, US FDA regulators, and biomedical company stakeholders. RESULTS: To date, there are 9 FDA-approved clinical trials of stem cell therapy for stroke. Safety and efficacy outcomes from these trials remain to be reported. CONCLUSIONS: Stem cell therapy for stroke remains an experimental treatment, and currently being tested in limited clinical trials. The need for transparent translational guidance on how to expedite the entry of this cell therapy to the clinic is warranted to abrogate the mortality and morbidity inherent in stroke. DISCLAIMER: CVB holds patents and patent applications related to stem cell therapy, and serves as consultant and editor to a number of stem cell-related biotech companies and scientific journals. Funded by NIH, Celgene, and Sanbio.
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O7. Chandran Cellular autonomy and neurodegeneration Siddharthan Chandran Centre for Multiple Sclerosis Research, MRC Centre for Regenerative Medicine, University of Edinburgh, Queens' Medical Research Institute, Edinburgh EH16 4TJ, UK. (Email: [email protected]). Neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease are characterised by the selective loss of specific neuronal subtypes. While the precise mechanisms underlying neuronal dysfunction and subtype specificity remain the subject of intense study, the cellular environment in which degenerating neurons reside has been shown to be an integral part of the disease. In turn, until comparatively recently glial damage and death has been the focus of other diseases such as multiple sclerosis. An emerging consensus across these diseases is that, dependent on context, glia can be injurious - setting the pace of, and perhaps in some instances initiating neurodegeneration - or even neuroprotective. My talk will discuss glial-neuronal interaction and the opportunities human stem cell systems offer to model aspects of cellular autonomy in the context of in the context of neurodegeneration – regeneration.
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O8. Duan AAV9-mediated EPO gene delivery in a rat model of Parkinson’s disease Wei-Ming Duan 1, Chun Yang 1, Yue-Qiang Xue 2, Ronald L. Klein 3, Li-Ru Zhao 4 1 Department of Anatomy, Capital Medical University, Beijing, China. 2 Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA. 3 Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA and 4 Department of Neurosurgery, Upstate Medical University, Syracuse, New York, USA. (Email: [email protected]). The aims of the work were to examine cellular and behavioral effects of intrastriatal injections of adeno-associated virus serotype 9 vectors - the human EPO gene (AAV9- hEPO) into the brain of 6-OHDA-lesioned rats, and to evaluate inflammatory and immune responses against AAV9-hEPO vectors in the striatum of the rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the substantia nigra. As a result, nigral dopaminergic neurons were protected against 6-OHDA- induced toxicity. Amphetamine- induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Intramuscular, but not intrastriatal injections of AAV9-hEPO resulted in reduced levels of hEPO transduction and increased levels of the major histocompatibility complex class I and class II antigen expression in the striatum following AAV9-hEPO re-administration. There were infiltration of the cluster of differentiation 4 (CD4)-and CD8-lymphacytes, and accumulation of activated microglial cells and astrocytes in the virally injected striatum. In addition, the sera from the rats with intramuscular injections of AAV9-hEPO contained greater levels of antibodies against both AAV9 capsid protein and hEPO protein than the other treatment groups. Acknowledgement: This work was funded by the Chinese Ministry of Science and Technology, and Beijing Natural Science Foundation.
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O9. Fawcett Targeting the extracellular matrix to repair the damaged nervous system James W. Fawcett Cambridge University Centre for Brain Repair, Robinson Way, Cambridge CB2 0PY, UK. (Email: [email protected]). Repair of damage to the nervous system requires axon regeneration, plasticity and cell replacement. The extracellular matrix plays a central role in restricting these processes, mainly through the action of chondroitin sulphate proteoglycans (CSPGs). An important agent in removing this restriction has been the enzyme chondroitinase, which removes glycosaminoglycan (GAG) chains from CSPGs. CSPGs are up-regulated in glial scar tissue around injuries to restrict axon regeneration, which can be enhanced with chondroitinase. However the positive effect of chondroitinase on functional recovery is mostly through reactivation of plasticity. Chondroitinase treatment enhances recovery from many forms of CNS damage, including spinal cord injury, where the reactivation of plasticity enables successful rehabilitation. Chondroitinase also has profound effects on memory, prolonging object memory in normal animals and restoring memory in an Alzheimer’s model. CPSGs control plasticity mainly through their participation in perineuronal nets (PNNs), cartilage- like structures surrounding neurons, which appear as critical periods for plasticity close. PNNs contain inhibitory CSPGs, hyaluronan, link protein and tenascin-R, partly produced by the neurones themselves and partly by surrounding glial cells. All neurones with PNNs express both a hyaluronan synthase enzyme and a link protein, and these are the key components that trigger the formation of the structures. Link protein knockout animals lack normal PNNs on their dendrites, and these animals retain plasticity into adulthood, and show prolongation of memory identically to animals treated with chondroitinase. The action of the CSPGs is due to their sulphated GAGs. In the CNS these bind to and localise Semaphorin3A and OTX2 to PNNs. OTX2 is involved in the maturation of inhibitory interneurons, while Semaphorin3A is an effector of the PNNs involved in control of plasticity.
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O10. Gernert Grafting of rat and porcine fetal neuronal cells into the subthalamic nucleus in experimental epilepsy Gernert M 1,2, Petersen B 3, Gey L 1,2, Handreck A 1,2, Löscher W 1,2, Niemann H 3 and Backofen-Wehrhahn B 1 1 Dept. of Pharmacology, Toxicology, and Pharmacy, University of Vet. Medicine, 2 Center for Systems Neuroscience, Hannover, Germany, 3 Inst. of Farm Animal Genetics, Friedrich- Loeffler-Inst., Mariensee, Germany. (Email: [email protected]). Neuronal transplantation into brain regions involved in seizure generation or propagation is a promising experimental approach to treat drug-resistant epilepsies. We recently showed that the subthalamic nucleus (STN) might be a promising target region in this respect (Bröer et.al. 2012, Neurobiol Dis. 46: 362-376). We now tested two types of rat and porcine fetal stem cells (RNSCs and PNSCs) isolated from: (A) medial ganglionic eminence (MGE), and (B) mesencephalon. Grafts of both cell types cultivated as neurospheres were inserted bilaterally into the STN (80,000 cells per side). Anticonvulsant efficacy was evaluated by testing seizure thresholds before and at different time-points after grafting (from 10 days up to 3 months). RNSCs and PNSCs derived from the mesencephalon, but not from the MGE, showed clear anticonvulsant effects ten days and moderate effects 3 months after grafting. PNSCs differentiated into neurons and astrocytes and showed expression of the GABA- synthesizing enzyme glutamic acid decarboxylase. These data indicate that grafting of neuronal mesencephalic stem cells into the STN could be a promising approach to treat epilepsy. Future work will focus on improving duration of anticonvulsant efficacy after grafting into the STN. Acknowledgment: Supported by the DFG (Ge1103/7-2)
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O11. Gill GDNF – Back in the clinic Steven S Gill 1, Neil Barque 1, Alison Bienemann 1, Max Woolly 1, Nik Patel 1, Matthias Luz 2, Lyn Barclay 2, Eric Mohr 2, Lucy Mooney 1, Elizabeth Coulthard 1, Andrew Lawrence 3, Chis Marshall 3 and Alan L Whone 1. 1 Neurosciences, Frenchay Hospital / North Bristol Trust, Bristol BS16 1LE, United Kingdom; 2 MedGenesis Therapeutix, Inc., Victoria, BC V8W 3Y7, Canada; and 3 Cardiff University, Cardiff, United Kingdom. (Email: [email protected]). Objective: To evaluate in PD the efficacy and safety of intermittent GDNF intra-putaminal infusions administered by Convection Enhanced Delivery. Background: In animal models of PD and in open label studies in PD patients, continuous intra-putaminal GDNF infusions have been shown to improve motor symptoms and, as assessed by 18F-dopa PET and post-mortem assessments, restore dopamine terminals. However, in 2003, a placebo-controlled multi-centre trial reported failure to demonstrate clinical benefit, despite improvements in PET end-points. In addition, a concurrent study in monkeys raised questions over safety. Since that point no further human investigations have been performed. In significant part, we believe, the above issues were due to a failure in the way GDNF was surgically delivered. We have now developed an in-house device which animal model studies suggest will allow GDNF to be given much more reliably to the putamen. We feel this allows for definitive testing of GDNFs effects in humans. Methods: A phase II, single centre, randomized, double blind, placebo-controlled trial, in idiopathic PD (n=42), of intermittent bilateral posterior putamen GDNF infusions administered via Convection Enhanced Delivery (CED) was commenced in 2012. The drug delivery system comprises 4 micro-catheters, with in-line filters, and a skull mounted transcutaneous drug delivery port with 4 independent channels. 4 programmable pumps are connected to the port via an administration set on a 2 or 4 weekly basis for intermittent infusions of GDNF or placebo ( aCSF ) through the course of this trial. Results: The design of this 3 phase trial: Pilot Stage; Primary Study stage; and Roll-Over Stage will be discussed as well as describing the technological challenges of achieving reliable intermittent CED of GDNF over the long term and how we are attempting to address these. Conclusions: This will be the first clinical study of intermittent GDNF infusions delivered by CED in man.
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O.12. Gowing Generation of human neural progenitor cells from induced pluripotent stem cells that survive, migrate and integrate into the rodent spinal cord Geneviève Gowing1, Dhruv Sareen1,2, Anais Sahabian1, Kevin Staggenborg1, Renée Paradis1, Pablo Avalos1, Jessica Latter1, Loren Ornelas1, Leslie Garcia1, Clive N. Svendsen1,2 1Regenerative Medicine Institute, 2Department of Biomedical Sciences, Cedars-Sinai Medical Center, AHSP 8th floor, 8700 Beverly Blvd., Los Angeles, CA 90048, US. (Email: [email protected]). Transplantation of human neural progenitors (hNPC) derived from pluripotent stem cells (PSC’s) is a promising therapeutic strategy that has the potential to replace lost cells, modulate the injury environment and create a permissive milieu for the protection or regeneration of host neurons in disease., Here we use a novel chopping technique to isolate and expand EZ spheres from PSC’s which were then driven to an expandable iNPC spinal cord phenotype using a combination of retinoic acid followed by the mitogens EGF and FGF-2. iNPCs grown in suspension showed similar characteristics to hNPCs derived from human fetal tissues, although iNPCs grown as an adherent culture did not. Suspension iNPCs were easy to maintain using the chopping method of expansion and survived grafting into the spinal cord of athymic nude rats with no signs of overgrowth, again with very similar profiles to hNPCs derived from fetal tissues. These results suggest that iPSC-derived NPC’s could be a favorable alternative to fetal hNPCs for cellular regenerative therapies of CNS diseases.
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O13. Gray Modulating endogenous stem cells to restore learning and memory in Temporal Lobe Epilepsy W.P. Gray Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales UK. (Email: [email protected]). Neurogenesis, the production of new neurons, is a restricted event in the adult human brain, largely confined to the dentate gyrus where it is important for hippocampal learning and memory. While early studies showed conflicting roles for neurogenesis in spatial learning & memory, more recent work using paradigms that involve a higher cognitive demand, have demonstrated roles for neurogenesis in both the acquisition and retrieval of spatial relational memory. Altered neurogenesis also appears to play a role in anxiety and depression. Interestingly antidepressants increase hippocampal neurogenesis, an effect that appears necessary for their behavioural effects on mood and anxiety. Hippocampal neurogenesis is affected by a myriad of factors from neural activity (learning), exercise, drugs, metabolism, the immune system as well as brain injury and disease. Altered neurogenesis may thus be an important mechanism, underlying cognitive dysfunction and altered mood across a wide variety of neurological diseases, and as such presents an attractive target for medical and surgical interventions. I will present on overview of hippocampal neurogenesis, followed by an analysis of how it is affected by temporal lobe epilepsy, and emerging strategies from our lab and others, on how it may be restored.
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O14. Hantraye Imaging stem cell fate following intracerebral grafting Philippe Hantraye Molecular Imaging Research Center (MIRCen) and URA CEA-CNRS 2210, Institute of Biomedical Imaging, 18 Route du Panorama, Fontenay-Aux-Roses 92268 FRANCE (Email: [email protected]). When paving the way towards clinical applications of stem cell grafting, one crucial step is the ability to ascertain whether once implanted in a particular individual the pre- differentiated stem cells are actually evolving normally. In fact, a longitudinal, non-invasive follow-up should help us predict whether cells giving rise to the expected neuronal cell type or, on the contrary, turning into an unnecessary mixture of neurons and/or glial cells or even leading to an uncontrolled growth of cells that would potentially be harmful to the patient. In vivo imaging may be helpful in solving these questions provided that each of the available modalities has been carefully validated and tested for its capacity to differentiate the normal and/or the pathological fate of the cells following grafting in a living being. In addition, as these techniques have to be applied to a clinical setting, their use should meet strict regulatory and safety criteria. Of all available techniques, magnetic resonance imaging (MRI) has been long used to obtain information about graft placement, the in vivo monitoring of graft growth as well as occurrence of abnormal phenomena either associated with the grafting procedure itself (mechanical stress, hemorrhages) or the potential death of the grafted cells occurring shortly following their implantation (oedema). Besides MRI, alternative MR techniques have also been developed and studied for their potential use in stem cell research to precise the fate of these cells in the living being. In this context, 1H-MR spectroscopy has proven capable of providing a biochemical signature of the graft composition in vivo, which helps differentiate a graft presenting with the expected proportion of neurons and another, undoubtedly enriched in astrocytes or other glial cell types. In addition, diffusion- weighted MR imaging may also yield invaluable information on how the grafted cells extend significant processes out of their implantation sites and efficiently reconnect remote regions of the host's brain in a normal or unexpected way. Most certainly, one of the imaging techniques that holds most promise in medical applications of stem cell research is positron emission tomography. This radioisotopic technique enables one to map and quantify the concentrations of any molecule previously labeled with a positron-emitting isotope. Depending on the radiotracer being selected for the study, PET can either serve as a means to detect adverse effects like neuroinflammation and cell rejection or to study the phenotypic differentiation of the graft using markers that are specific of the expected neuronal cell population. Metabolic
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markers like 18F-fluorodeoxyglucose can also help differentiate between surviving neurons and dying cells. Reuptake blockers like the cocaine analog 18F-LBT999 can also evidence the regrowth of presynaptic terminals, innervating de novo the grafted stem cells neo- differentiated into striatal GABAergic neurons. Very similarly, specific radiomarkers of the pre- and post-synaptic elements of the dopaminergic synapse can also be used to establish the functional status and the degree of integration of stem cells programmed to differentiate into a dopaminergic phenotype. When preparing a clinical trial, it is certain that a combination rather than the sole use of one of these imaging approaches has to be envisioned. Preclinical trials have also shown that the best combination of imaging techniques/markers may vary greatly in function of stem cell type to be used. Examples of the use of these various imaging techniques will be provided and their advantages and disadvantages will be discussed in the context of the preclinical application of stem cells for Huntington's and Parkinson's diseases.
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O15. Huang Global clinical neurorestoration in complete chronic spinal cord injury Hongyun Huang, Tiansheng Sun, Lin Chen, Milan Dimitrijevic, Gustavo Moviglia, Elena Chernykh, Klaus von Wild, Haluk Deda, Kyung-Sun Kang, Anand Kumar, Sang Ryong Jeon, Shaocheng Zhang, Giorgio Brunelli, Albert Bohbot, Maria Dolors, Jianjun Li, Alexandre Fogaça Cristante, Haitao Xi, Gelu Onose, Helmut Kern, Ugo Carraro, Hooshang Saberi, Hari Shanker Sharma, Alok Sharma, Xijing He, Dafin Muresanu, Shiqing Feng, Ali Otom, Dajue Wang, Koichi Iwatsu (all authors from 19 countries) Center of Neurorestoratology, Beijing Rehabilitation Hospital affiliated Capital Medical University, Beijing, China, 100144 (Email: [email protected]) Abstract It is still popular in medical community that there are no any effective therapeutic methods to restore neurological functions for lesion. Though the treatment to recover function in people suffering complete spinal cord injury (SCI) remains a big challenge for clinical physicians, accumulating data have shown that partial clinical neurorestoration is possible by using cell therapy, neurostimulation or neuromodulation, neuroprosthesis or related advanced assistive devices, neurotization or nerve bridging, neurorehabilitation. Here we summarize the literatures that demonstrate patients with chronic complete SCI have been able to obtain some clinical neurorestoration, which is based on the scientific information available till April of 2013, and we discuss several important issues about these evidences. The goal of this review is to show the objective “yes or no” evidences of clinical neurorestoration for chronic complete SCI, which will make more people know real progresses in this field. And we hope the medical community is able to highlight the value of clinical neurorestorative treatments for CNS incurable diseases.
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O16. Kefalopoulou Very long-term clinical outcome of fetal cell transplantation for Parkinson’s disease Zinovia Kefalopoulou1, Marios Politis2, Paola Piccini2, Niccolo Mencacci3, Kailash Bhatia1, Marjan Jahanshahi1, Håkan Widner4, Stig Rehncrona5, Patrik Brundin6,7, Anders Björklund8, Olle Lindvall4, Patricia Limousin1, Niall Quinn1, Thomas Foltynie1 1 UCL Institute of Neurology, National Hospital for Neurology & Neurosurgery, Queen Square, London, UK; 2 Department of Medicine, Hammersmith Hospital, Imperial College London, UK; 3 Reta Lila Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, London, UK; 4 Division of Neurology; and 5 Neurosurgery, Department of Clinical Sciences, University Hospital, Lund, Sweden; 6 Van Andel Research Institute, Center for Neurodegenerative Science, Grand Rapids, Michigan, USA; 7 Neuronal Survival Unit; and 8 Neurobiology Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. (Email: [email protected]). Recent advances in stem cell technologies have renewed an interest in the use of cell replacement strategies for patients with Parkinson’s disease (PD). This study reports the very long-term clinical outcomes of fetal cell transplantation in two patients with PD. Such long-term follow-up data can usefully inform on the potential efficacy of this approach, as well as the design of trials for its further evaluation. Two patients received intrastriatal grafts of human fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, as restorative treatment for their PD. To evaluate the long- term efficacy of the grafts, clinical assessments were performed 18 and 15 years post- transplantation. Motor improvements developed and increased gradually over the first post-operative years, and are sustained up to 18 years post-transplantation. Despite each patient having nearly 30-years of PD with troublesome fluctuations and dyskinesias prior to transplantation, both patients now present with mild symptoms, and are independent of any pharmacological dopaminergic treatment for more than 10 years. Both patients have developed mild/moderate graft-induced dyskinesias. The results from these two cases indicate that dopaminergic cell transplantation can offer very long-term symptomatic relief in carefully selected PD patients, and provide proof-of- concept support for future clinical trials using fetal or stem cell therapies. Acknowledgements: This work was supported in part by the European Commission under the 7th Framework Programme – HEALTH – Collaborative Project Transeuro (Contract n°242003).
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O17. Kidd Anti-amyloid precursor protein antibodies as a potential therapy for Alzheimer’s disease Emma J. Kidd1, Martha Hvoslef-Eide1,2 and Rhian S. Thomas1 1School of Pharmacy and Pharmaceutical Sciences, 2School of Psychology, Cardiff University, Cardiff, UK (E-mail: [email protected]). Cleavage of amyloid precursor protein (APP) by β- and γ-secretases results in amyloid-β (Αβ) production in Alzheimer’s disease. We raised two antibodies to the β-secretase cleavage site in APP. Our hypothesis was that these antibodies would reduce Aβ levels via steric hindrance of β-secretase. Cells were incubated with various antibodies and APP, its cleavage fragments and the affinities of the antibodies for binding to the cleavage site and likely epitopes were measured by ELISAs. The ability of antibodies to enter cells was examined by immunocytochemistry. Block of β–secretase by steric hindrance was investigated. Both antibodies significantly reduced Aβ levels with 2B3 being more effective than 2B12. 2B3 had higher affinity for the β–secretase cleavage site than 2B12 and bound across the cleavage site while 2B12 bound upstream. Both antibodies entered living cells and inhibited the action of β–secretase. 2B3 is a more potent antibody than 2B12 to reduce Aβ levels in agreement with its higher affinity for the cleavage site and epitope location. We have proved our hypothesis that these antibodies block the β-secretase cleavage site. 2B3 is being considered as a therapeutic antibody for Alzheimer’s disease. Acknowledgement: This work was funded by the Alzheimer’s Society.
45 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O18. Lelos Human ventral mesencephalic grafts alleviate both motor and non-motor dysfunctions in a rodent model of PD Mariah J. Lelos, Claire M. Kelly, Eduardo M. Torres, Anne E. Rosser and Stephen B. Dunnett Brain Repair Group, School of Biosciences, Cardiff University, UK. (Email: [email protected]). Although it remains the current ‘gold standard’ cell replacement therapy, characterisation of the functional efficacy of human primary tissue is currently limited to the alleviation of simple motor deficits. Given that Parkinson’s disease patients also develop impairments in a range of non-motor domains, including neuropsychiatric and cognitive deficits, it is critical to evaluate the cell therapies in terms of their impact upon these non-motor dysfunctions. To address this, we pre-trained rats on a lateralised reaction-time task, before they received a unilateral 6-OHDA MFB lesion. A subset of lesion rats were then grafted with suspensions of human ventral mesencephalic tissue (hVM), of ~9 weeks gestation. On both amphetamine- and apomorphine-induced rotation tests, rats grafted with hVM displayed a significant reduction in rotational bias. Twelve weeks post-graft, rats were tested on two distinct versions of the operant task. Results from grafted rats revealed enhanced motor function (movement time, reaction time) as well as significant improvement of non-motor impairments, including motivational and spatial processing (total trials completed, accuracy). These data are the first to demonstrate that VM tissue from the human fetus is capable of alleviating the non-motor dysfunctions induced by loss of striatal dopamine in Parkinson’s disease. Acknowledgement: Funded by FP7 NeuroStemCell
46 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O19. Li Directing striatal GABAergic fate specification of human pluripotent stem cells Charles Arber, Sophie V. Precious, Serafí Cambray, Jessica R. Risner-Janiczek, Claire Kelly2, Andreas Heuer, Tristan A. Rodríguez, Anne E. Rosser, Stephen B. Dunnett and Meng Li Neuroscience and Mental Health Research Institute, Cardiff University. (Email: [email protected]). The -amino butyric acid (GABA) medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum, which specifically degenerate in the early phase of Huntington’s disease. Unlike some other neurodegenerative diseases, such as Parkinson’s, which can be effectively managed for years by dopamine-based pharmacotherapy, no effective treatment is currently available for Huntington’s. MSNs derived from human pluripotent stem cells (hPSCs) promise hope for developing transplantation-based cell therapy, studying disease aetiology and drug screening for HD. We discovered that the TGFβ molecule activin can induce lateral GE (LGE)/striatal characteristics in forebrain neural progenitors derived from hESCs and hiPSCs. These progenitors readily differentiate into post-mitotic neurons expressing the signature marker of MSNs, dopamine- and cAMP- regulated neuronal phosphoprotein (DARPP32) in culture, as well as following transplantation into the striatum of a rat model of Huntington’s disease. Significantly, grafts derived from activin A-induced striatal progenitors showed no cellular expansion and were tumour-free 16 weeks post-transplantation. Together, our findings demonstrate a novel route for directed differentiation of transplantable MSNs from hPSCs.
47 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O20. Mochizuki Gene therapies for hereditary Parkinson’s disease; a strategic transition from in vivo to ex vivo Hideki Mochizuki Department of Neurology, Osaka University, Osaka, Japan. (E-mail: hmochizuki@neurol. med.osaka-u.ac.jp). In mouse and monkey models of Parkinson’s disease (PD), we have previously shown that intracerebral injection of adeno-associated viral vector encoding parkin, which is the causative gene of autosomal-recessive juvenile-onset PD PARK2, resulted in rescue of neuronal and behavioral phenotypes (1,2). Delivery of parkin counteracted the attenuation of PKB/Akt pathway and protected dopaminergic neurons from apoptotic death in PD mice (2). However, the proportion of neuronal survival was limited to a small extent and mitochondrial abnormality was not corrected in the in vivo gene therapy. Meanwhile, a recent advances on iPS cell technology led us to establishment of a novel ex vivo gene therapy for hereditary PD. We have generated dopaminergic neurons in vitro from iPS cells, derived from PARK2 patients, and found mitochondrial dysfunction and accumulation of alpha-synuclein, which resembled the histopathology in a donor patient (3). We are studying the effects of transduction of wild-type parkin to the parkin-deficit iPS cell-derived dopaminergic neurons and transplantation of these cells in mouse and monkey models of PD to evaluate the novel ex vivo gene therapy. (1) Yamada et al., Hum Gene Ther 2005. (2) Yasuda et al., J Neuropathol Exp Neurol 2011. (3) Imaizumi et al., Mol Brain 2012.
48 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O21. Monville Clinical application of retinal pigment epithelium (RPE) cells derived from human embryonic stem cells Karim Ben M’Barek 1*; Walter Habeler 1* ; Alexandra Plancheron 1 ; Ying Yang 2 ; Mohamed Jarraya 3 ; José-Alain Sahel 2 ; Marc Peschanski 1 ; Olivier Goureau 2 ; Christelle Monville 1 1. INSERM/UEVE UMR861, IStem, AFM, Évry, France; 2. INSTITUT DE LA VISION, INSERM U968, 17 rue Moreau, Paris, France; 3. Banque de Tissus Humains, Hôpital St Louis, Paris, France. (Email: [email protected]). * These authors contributed equally to this work.. The retina is part of the central nervous system and contains specialized neurons, photoreceptors, that convert light signals into electric signals, further transmitted to the brain by different neurons. In vivo, the retinal pigmented epithelium (RPE) constitutes a distinct monolayer of pigmented cells lying between the neural retina and Bruch’s membrane, which provides essential support for the long-term preservation of retinal integrity and visual function. Given the intimate anatomical and functional relationship of RPE cells and photoreceptors, it is not surprising that the first manifestations of primary RPE disorders are problems with visions. Such is the case with age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP) caused by mutations in genes involved in central RPE functions. RPE replacement therapies using RPE cells generated from human embryonic stem cells (hESC) provide a novel approach to a rational treatment of such forms of blindness. The aims of our study is to (i) generate a clinically- compatible polarized monolayer of RPE cells derived from human embryonic stem cells (hESC) disposed on a biocompatible membrane and (ii) test their functional properties in RP animal models in order to develop a clinical trial for patients suffering from genetic RPE disorders. The clinical grade hESC line, RC-09 (Roslin Cells, Edinburgh, Scotland) is used for RPE differentiation. Our laboratory already set up and validated a reproducible differentiation protocol to generate pure RPE cells from several human pluripotent stem cells including RC-09. RPE cells obtained are polarized and functional. Our method is robust and productive: a single six-well plate of hESCs can generate 8x107 RPE cells. This protocol should now be adapted for clinically compatible conditions.
49 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O22. Newland Encapsulation of stem cells in an in situ gelling collagen hydrogel improves graft volume and striatal retention after intra-cerebral transplantation in the rat Ben Newland 1, Deirdre Hoban 2, Abhay Pandit 1 and Eilís Dowd 2 1 Network of Excellence for Functional Biomaterials, and 2 Pharmacology & Therapeutics, National University of Ireland Galway, Ireland. (Email: [email protected]) Delivery of neurotrophic factors to the brain via genetically modified mesenchymal stem cells (MSCs) offers a promising neuroprotective strategy for neurodegenerative diseases. However, MSCs delivered to the CNS typically show poor survival post transplantation which limits their therapeutic efficacy. Recent studies have revealed the potential of biomaterials as supportive matrices for transplanted cells which may assist in the grafting process. In this study, an in situ gelling type I collagen hydrogel was evaluated as an intracerebral transplantation matrix for delivery of MSCs to the rat brain. We specifically investigated the effect of the hydrogel on striatal graft volume and retention. Preliminary in vitro studies confirmed that the hydrogel was neither non-toxic to MSCs seeded within it nor to neural cells seeded in juxtaposition to it. We then demonstrated that the collagen hydrogel itself was well tolerated in the rat brain, and was capable of improving the volume of the MSC graft after transplantation. Moreover, the hydrogel completely prevented ectopic deposition of MSCs along the needle track thereby increasing striatal retention of the graft. These findings indicate the potential of supportive hydrogels for intra-cerebral cell transplantation studies. Acknowledgement. This work was funded by Science Foundation Ireland
50 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O23. Palfi Prosavin, a dopamine gene therapy for advanced PD: phase I clinical update Palfi S3, Gurruchaga J-M3, Ralph GS2, Watts C4, Buttery P4, Scorer S2, Lepetit H3, Miskin J2, Iwamuro H3, Lavisse S1, Kas A1, Ramelli A.L3, Tani N3, Dolphin P3, Fenelon G3, Brugiere P3, Kingsman S2, Naylor S2, Barker R4, Hantraye P1, Remy P1,3, Césaro P3 , Mitrophanous K2 1 CEA-CNRS MirCen Fontenay aux Roses France ; 2 Oxford BioMedica (UK) Ltd, Oxford Science Park, Oxford, UK; 3 Henri Mondor Hospital, Paris University, France; 4 Addenbrooke’s hospital, Cambridge, UK. (Email : [email protected]). Parkinson’s disease (PD) is a neurodegenerative disease that results in a progressive degeneration of dopaminergic neurons. The dopamine precursor L-Dopa and dopamine agonists provide the primary standard of care and demonstrate good therapeutic benefit in the early stages of disease. However, their long term use is associated with severe motor side effects that are at least partially caused by the fluctuating nature of dopaminergic stimulation that arises from oral drug administration. As such, a therapy that provides a more continuous and local supply of dopamine to the site of pathology provides a potential approach for the development of new therapeutic strategies. ProSavin® is a gene therapy product that utliises a lentiviral vector to transfer three genes that are critical for dopamine biosynthesis to the the striatum, that is depleted of dopamine in PD. Clinical evaluation of the safety and efficacy of ProSavin in mid to late stage PD patients is currently ongoing. In the study fifteen patients have received ProSavin® in three dose cohorts. ProSavin® has been demonstrated to be safe and well tolerated at all doses evaluated to date. There have been no serious adverse events related to Prosavin® or the administration procedure and no inflammatory responses. In terms of efficacy an improvement in the primary endpoint, UPDRS Part III, has been observed in all cohorts relative to their baseline scores. Furthermore, an improvement has been maintained out to the latest timepoints evaluated to date (up to 4 years for the earliest cohort). Secondary endpoints including the patients concommitant dopaminergic medications has also demonstrated improvements.
51 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O24. Parmar Generating neurons for use in cell therapy; challenges and possibilities Agnete Kirkeby, Ulrich Pfisterer, Jenny Nelander, Shane Grealish, and Malin Parmar Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 221 84 Lund, Sweden. (Email: [email protected]). Parkinson’s Disease (PD) is a particularly interesting target for stem cell based therapy. The central pathology is confined to a small group of neurons in the midbrain, the nigral dopamine (DA) neurons and their projection to the striatum. Transplants of DA neurons could be used to restore DA neurotransmission in the striatum, substitute for the lost neurons, and bring back normal motor behavior. Proof-of-principle that this can work has been obtained in trials where fetal DA neuroblasts, have been transplanted to the putamen in patients with advanced PD. Despite these encouraging results, work with human fetal tissue presents a number of ethical and logistical problems and therefore does not represent a realistic therapeutic option in the future. Further progress in this field is critically dependent on the development of a bankable and renewable source of transplantable DA neurons. We have developed a method to generate human neural progenitors and neurons from human embryonic stem cells (hESCs), which recapitulates human fetal brain development. By addition of a small molecule to activate canonical WNT signalling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. The DA neurons obtained via our protocol closely resembled their fetal counterparts, making them useful as a model system for studies of human fetal brain development and also for developing transplantable therapeutic cells. In parallel, we also develop cell reprogramming as an alternative source of neurons. We have found that the neural conversion genes (Mash1, Brn2a, Myt1l) can convert human fibroblasts into induced neurons (iNs). When combined with DA fate determinants, functional DA neurons can be obtained with this technique.
52 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O25. Ramsden Experimental and clinical transplantation of pluripotent stem cells for cell therapy in retinal disease Conor M. Ramsden 1,2, Michael B. Powner 1, Amanda-Jayne F. Carr 1, Matthew J. K. Smart 1, Lyndon da Cruz 1,2, Peter J. Coffey 1, 3 1 The London Project to Cure Blindness, Division of ORBIT, Institute of Ophthalmology, University College London, 11–43 Bath Street, London, EC1V 9EL, UK; 2 NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation; Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK. 3 Center for Stem Cell Biology and Engineering, NRI, UC Santa Barbara, US. (Email: [email protected]). Several clinical trials of cell based therapy for retinal degeneration are currently recruiting worldwide. This clinical translation is based on over a decade of research into retinal development and physiology. One approach is to generate an appropriate replacement from stem cells, another is to use their paracrine restorative qualities. In tandem, surgical research into autologous retinal transplantation has evolved techniques to manipulate grafts into the subretinal space. The eye is an ideal organ for an experimental cell based therapy due to its transparency and the immune privilege conferred by the blood retina barrier. The first trials have focussed on the replacement of the retinal pigment epithelium but ultimately elements of the neural retina must be transplanted to address diseases such as advanced age related macular degeneration and retinitis pigmentosa. Medium and long term follow up of these trials is eagerly awaited.
53 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O26. Rinaldi Differentiation of human pluripotent stem cells into brain-regionalized astrocytes to investigate pathogenesis of Parkinson’s and Alzheimer’s diseases Federica Rinaldi, Jennifer Badger, Lucy Crompton and Maeve Caldwell1 1School of Clinical Sciences, Bristol University, UK . (Email: [email protected]). Progressive neuronal degeneration and loss are hallmarks of several neurodegenerative disorders including Parkinson’s (PD) and Alzheimer disease (AD); with aetiology and pathophysiology of disease progression not yet fully elucidated. In this study we describe the generation of multipotent neural progenitor (NPs) cells from human stem cells including embryonic (hES) and induced pluripotent (iPS) cells. Our protocol faithfully recapitulates in vivo neurogenesis where neurons are generated first followed by astrocytes. We have employed RNA and protein analysis to characterize the transition from pluripotent to NP cells, and to more restricted astroglial progenitors. Ultimately, mimicking morphogen gradients occurring in vivo during neural development we have patterned NP cells to acquire basal forebrain and ventral midbrain identity thus successfully deriving brain-regionalized astrocytes. Our results reflect novel data, which have indicated the presence of heterogenic astrocytes distinguished according to their morphology, function, electrical proprieties and transcriptome. Furthermore our protocol will be of particular interest in the elucidation of the participation of regional astrocytes in neurodegenerative disorders that affect a specific brain region such as PD and AD, previously understood as exclusively neuronal disorders. Acknowledgement. This work was funded by Parkinson’s UK.
54 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O27. Rylander Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism Rylander Daniella 1,2, Bagetta Vincenza 2, Pendolino Valentina 2, Zianni Elisa 3, Gardoni Fabrizio 3, Di Luca Monica 3, Calabresi Paolo 2,4, Cenci Maria Angela 1 and Picconi Barbara 2. 1 Lund University, Lund, Sweden; 2 Fondazione Santa Lucia, IRCCS, Rome, Italy; 3 Università degli Studi di Milano, Milan, Italy; 4 Università degli studi di Perugia, Perugia, Italy. (Email: daniella.rylander@med. lu.se). Intrastriatal transplantation of dopaminergic neurons can restore dopamine levels and improve parkinsonian deficits. However, underlying mechanisms are poorly understood. Here we evaluated the synaptic plasticity in the host striatum after neural transplantation using a rat model of Parkinson’s disease. Naïve rats showed distinct synaptic plasticity patterns in striatum. Ventrolateral striatum showed long-term potentiation (LTP) in approximately 63% of the neurons using the same protocol that elicited long-term depression (LTD) in the dorsolateral striatum. The LTP was linked to higher expression of post-synaptic AMPA- and GluN2B NMDA subunits and was shown not to be pathway dependent. In both regions, the synaptic plasticity was abolished after dopamine-depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine grafts restored the LTP and partially restored motor deficits. The restoration was only present in ventrolateral striatum where grafted re-innervation was denser compared to the dorsolateral region. These data provide a first proof of concept that dopamine transplants are able to functionally integrate into the host brain and restore neuronal deficits in striatal synaptic plasticity after experimental PD. This might have implications for the limitation in symptomatic improvement following transplantation. This work was funded by Swedish Research Council (BAGADILICO), European Community (222918, 7th framework, REPLACES), Tegger Foundation (Sweden).
55 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O28. Shelley Clinical-grade neural progenitor cells secreting GDNF for the treatment of ALS Brandon Shelley±, Genevieve Gowing±, Jessica Latter, Kevin Staggenborg, Pablo Avalos, Leslie Garcia, Renee Paradis, Maximus Chen, Amanda Hurley, Jessica Zelaya, Clive Svendsen. Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA. (± Co-Authors; Email: [email protected]) Amyotrophic Lateral Sclerosis (ALS) is a disease in which motor neurons die due to an unknown mechanism. Human, fetal cortex-derived neural progenitor cells (hNPCs) can be expanded in vitro and survive and integrate into large and small animals following transplantation, such as rat models of ALS. Furthermore, hNPCs can be genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF), a powerful growth factor that has been shown to have a neurotrophic effect in animal models. We have demonstrated that transplanting hNPCs engineered to secrete GDNF can rescue the microenvironment and preserve dying motor neurons in animal models of ALS. Moving towards the clinic, we have generated a GMP-grade master cell bank of hNPCs and sourced it to generate research and clinical-grade cell lots transduced to secrete GDNF with GMP-grade lentivirus. We have completed the dose ranging aim of the project using an ALS rat model and are moving forward with the safety/toxicity aim required by the FDA for approval of a phase 1/2a drug safety trial. Here we show the progress made over the first six months of the project and describe future plans, with the eventual goal of transplanting 18 patients. Acknowledgement: CIRM DR2A-05320.
56 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O29. Sladek From Thompson to Hopkins-Dunn to Ranson; if the Pioneers could see us now! John R. Sladek, Jr. Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA. (E-mail: [email protected]). At the first of the series of twelve international meetings on neural transplantation (and now repair) near Lund in 1984, Professors Björklund and Stenevi presented a thoughtful review of the history of our field and drew attention to the findings of early investigators such as Thompson (1890), Faldino (1924), Flerko (1957) and others. At our second meeting (Rochester, 1987) we explored the great progress achieved by our modern pioneers including ongoing clinical experiments and new models of neurological diseases amenable to repair. Clearly W. G. Thompson (NYU) should be credited with the first attempt to graft brain tissue and remarkably in 1909, Walter Ranson (Northwestern Univ.) succeeded in grafting spinal ganglia and observed signs of neuronal plasticity. He described “factors” that must be controlling this cellular transformation, but lamented that there were no known means by which to identify them. Perhaps I’m biased, but Elizabeth Hopkins Dunn may have made the most important of these early discoveries by grafting comparatively young tissue to the adult brain and at a time when women scientists and physicians were rare and subjected to formidable obstacles to success. After graduation from the Iowa (now Grinnell) College in 1892, Dr. Dunn received her medical degree from the Northwestern University Women’s Medical School in 1894 and joined the faculty of the University of Chicago until 1906 when she moved to Woods Hole Marine Biological Laboratories, where her work extended to many other fields including publishing and cartography. On January 2, 1914 at the 29th annual meeting of the American Association of Anatomists in Cleveland she was the only woman among 13 other scientists in her morning session and presented her findings on “Transplantation of the cerebral cortex of the albina rat.” Her research revealed that the age of the donor tissue was critical and that neonatal tissue could survive in an adult brain. Her hand drawings of the host rat brain showing the presence of new neurons and neurites were both artistic and meaningful, and undoubtedly led to thousands of subsequent publications that utilized developing neural tissue to explore the potential for repair of neurological diseases and disorders. While so many others have made profound discoveries well beyond the scope of these early works, that Dr. Hopkins-Dunn was able to move our field forward amidst professional and likely personal obstacles suggests a brilliant mind and a persistent personality of this “First Lady of Neural Transplantation.” Acknowledgement. Special appreciation to NIH since 1974, ASNTR since 1994 and Grinnell College, Northwestern University, New York University, and the University of Chicago for their historical insights on our early pioneers.
57 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O30. Smith Rab1A and Rab3B gene therapy in the Q175 knock in model of Huntington’s disease Gaynor A. Smith, Emily N. Mangano, Melissa Hayes, Jesse R. McLean, Jonathan Beagan, Sara C. Izen, Ole Isacson and Penelope J. Hallett Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA, USA. (Email: [email protected]). Regulation of synaptic function, vesicular transport and organelle dynamics is fundamental to the normal function of the neuron. These processes are dysregulated in many neurodegenerative diseases prior to cell death, therefore providing a target for therapeutic intervention at early stages. Synaptic dysfunction and disturbances in protein transport and energy homeostasis have been reported in Huntington’s disease (HD) patients, and in experimental models with a CAG expansion in the huntingtin gene. These changes are modulated by specific direct and indirect protein interactions with huntingtin and the cytoskeleton, synapses and organelles, leading to both gain and loss of function. We have previously shown that delivery of Rab3b by gene therapy can improve neurotransmitter handling and storage capacity at presynaptic terminals, and prevent synaptic neurodegenerative changes in the dopaminergic system. We hypothesize that modulation of early pathophysiological changes by Rab proteins can enhance neuronal function in experimental models of HD. We first examined motor and cognitive functional deficits, biochemical changes, inflammation, inclusion formation, and the dysregulation of multiple proteins involved in synaptic and axonal transport, in a novel Q175 knock in (Q175 KI) mouse model of HD at 1, 6, 12 and 16 months of age. Q175 KI mice exhibited motor and cognitive deficits at 12 months, which were paralleled to striatal atrophy and microglial activation. Intracellular inclusions of mutant huntingtin were present from 6 months of age. Striatal GABA levels were increased at 1 and 6 months and a reduction in striatal dopamine observed from 6-16 months. Levels of proteins involved in synaptic and cellular transport functions were differentially altered in the striatum, motor cortex, pre- frontal cortex and hippocampus at 12 months, including a reduction of the synaptic vesicle protein Rab3B, and of the ER to golgi transport protein Rab1A, in cortical regions. We are currently testing whether intra-cortical and intra-striatal gene therapy of AAV2/5 Rab1A and Rab3B in Q175 KI mice will improve secretary transport and synaptic functions of the corticostriatal pathway, thereby preventing key pre-degenerative changes associated with HD. Funding: CHDI Foundation
58 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
O31. Snyder 1 Midkine (MDK): a newly-recognized endogenously-produced cytokine that, through an autocrine mechanism, is pivotal for neural induction I. Singec, A.M. Crain, B.T.D. Tobe, J. Hou, M. Talantova, K.S. Doctor, J. Choi, X. Huang, G. J. Gutierrez, D.A. Wolf, S.A. Lipton, L.M. Brill and E.Y. Snyder Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. (Email: [email protected]). Having devised a novel strategy for deriving pure neuroectoderm from human embryonic stem cells (hESCs), we performed the largest differential (phospho)proteomic analysis on any biological system to date, comparing hESCs with their neural stem cell (hNSC) derivatives to determine the key molecules responsible for neuralization & the transition from pluripotency to multipotency. Unexpectedly, MDK was exceptionally abundant where pluripotency marker OCT4 was receding, its expression highest in hNSCs. Though exogenous MDK promoted “neural tube” formation, endogenous MDK constitutively produced by the colony itself & acting upon receptors on OCT4+ cells in an autocrine fashion was sufficient to yield pure PAX6+ multipotent hNSCs (which could mature into electrophysiologically-active anterior dorsal cortical interneurons, which became caudalized with time, as well as other more specialized neural lineages, including glia, and motor and dopaminergic neurons). Inactivation of endogenous MDK (via neutralizing antibodies or shRNA-mediated knockdown) blocked neuralization. As suggested by the dataset and experimentally validated, MDK’s neural induction was mediated in part by PI3K/AKT/mTOR signaling, the inhibition of which disrupted neuralization and shifted hESC fate towards endoderm. Taken together, the (phospho)proteomic dataset and the confirmatory experiments above provide insights into a heretofore unrecognized mechanism critical to the emergence of neuroectoderm.
59 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O32. Tabrizi TRACK-HD and TRACK-ON HD – yielding new insights into Huntington’s disease Sarah Tabrizi UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. (Email: [email protected]). Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegen- erative disease for which there is currently no effective disease modifying therapy. The genetic predictability of HD provides an opportunity for early therapeutic intervention many years before overt symptom onset and at a time when reversal or prevention of neural dysfunction may still be possible. As HD is monogenetic, fully penetrant, and characterised by a long premanifest phase, it is emerging as a potential model for studying therapeutic intervention in other neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease where no preclinical diagnostic tests exist. Understanding of HD pathogenesis is evolving, and there are a number of candidate therapeutics with potential disease-modifying effects that are currently being tested. The most promising approaches will be briefly reviewed. Since 2008 TRACK-HD has chronicled the earliest stages of the neurodegenerative disease processes in premanifest and mild to moderately symptomatic individuals who carry the HD expansion mutation (Tabrizi et al, Lancet Neurology 2009, 2011). TRACK-HD was designed to observe natural disease progression in premanifest and early stage HD with the aim of understanding the preclinical and early phases of neurodegeneration, phenotypic correlates of neuronal dysfunction and to establish sensitive and specific clinical and biological markers of disease progression. In 2012, we reported longitudinal effect sizes for disease-progression in early stage HD over 24 months (Tabrizi et al, Lancet Neurology 2012). Both our 24 month and recently published 36 month time-point data will be presented (Tabrizi et al, Lancet Neurology 2013), including new insights into predictors of HD progression in both premanifest and early stage subjects, and a range of novel clinical measures that now show significant change in the premanifest group over this period. We have also identified baseline predictors of disease progression which may help enrichment for future disease-modifying clinical trials. We are now in a position to model progression in a range of functional, biochemical and imaging measures across the spectrum of disease. Finally I will summarise our ongoing research aiming to identify neural compensatory networks that may occur in the premanifest phase of neurodegeneration in HD, and dissection of the role of the innate immune system as a key modifier of disease progression.
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O33. Tuszynski Growth factor gene therapy for Alzheimer's disease: NGF and BDNF Mark H. Tuszynski Director, Translational Neuroscience Institute, Department of Neurosciences, University of California – San Diego, Veterans Affairs Medical Center, La Jolla, CA 92903. (Email: [email protected]). Nervous system growth factors have extensive effects on neuronal function and survival. Nerve growth factor (NGF) prevents the death and stimulates the function of basal forebrain cholinergic neurons in correlational models of Alzheimer’s disease (AD), leading to its translation to Phase 1 and 2 human clinical trials. Separately, Brain-Derived Neurotrophic Factor (BDNF) influences the survival and function of entorhinal cortical and hippocampal neurons in several animal models of AD, including transgenic mutant APP- expressing mice; aged rats and lesioned rats; and aged and lesioned primates. Thus, BDNF therapy has the potential to specifically target memory deficits in AD. The beneficial effects of growth factors in AD models appear to occur independently of detectable alterations in beta amyloid load, providing therapeutic alternatives to Aß-modifying therapies in AD. This lecture will provide an update on the current status and future directions of neurotrophic factor therapies that are in preclinical and clinical development.
61 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O34. Verfaillie Adult stem cell-based therapy for ischemic stroke Catherine M. Verfaillie Stem Cell Institute, KU Leuven, B-3000 Leuven, Belgium. (Email: [email protected]). Neural stem cells or neural stem/progenitor cells differentiated from pluripotent stem cells can generate neurons, astrocytes and oligodendrocytes, which could be used for regeneration of lost neural tissue following stroke, even if this has yet to be accomplished. Other cell populations are also being considered for therapy of stroke. We will describe the potential of (stem) cells from non-neural postnatal tissues, such as bone marrow, which themselves do not (or maybe in a very limited manner) generate neural progeny. However, these non-neuroectoderm derived cell populations may induce endogenous neurogenesis and angiogenesis, as well as have immunomodulatory properties that improve stroke outcomes. Preclinical animal studies (and pitfalls), early clinical studies, and possible mechanisms of action, as well as possible unforeseen complications will be discussed.
62 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
035. Vanderhaeghen From pluripotent stem cells to cortical circuits: perspectives for disease modelling and brain repair Pierre Vanderhaeghen WELBIO, IRIBHM and ULB Neuroscience Institute, Université Libre de Bruxelles, Belgium. (Email: [email protected]). The cerebral cortex consists of several hundreds of different types of neurons, organized into specific cortical layers and areas, that display specific profiles of gene expression, morphology, excitability and connectivity. Embryonic stem (ES) and other pluripotent stem cells constitute a promising tool for the modelling and treatment of human neural diseases. Here we describe an intrinsic pathway by which pluripotent stem cells, whether of mouse or human origin, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of pyramidal neurons that display most salient features of genuine cortical neurons. Interestingly, the mouse and human pathways of corticogenesis display many similarities but also striking differences that may be related to species-specific developmental programmes. When transplanted into the cerebral cortex of new-born mice, the ESC-derived cortical neurons develop specific patterns of axonal and dendritic projections corresponding to endogenous cortical projections in vivo. Following transplantation into lesioned adult mouse cortex, the grafted neurons also establish robust and specific long range projections and synapses corresponding to cortical circuits. These data shed new light on the mechanisms of neuronal specification, and constitutes an innovative tool to model human cortical development, evolution, and disease, in vitro and in vivo. In the long run, cortical neurons generated in vitro could be used also in the perspective of brain repair, for several diseases striking cortical neurons.
63 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
O36. Wright Production of new striatal neurons in the healthy and diseased neonatal brain Wright J, Thompson LH 1The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia. (E-mail: [email protected]). Substantial advances have been made in the last decade on our understating of the basic physiology underlying neurogenesis in the postnatal mammalian brain. The bulk of the work in this area has been based on analysis of the adult brain. Relatively less is known about the capacity for neurogenesis in specific structures within the neonatal brain. Here we demonstrate that the production of medium spiny striatal projection neurons (MSNs) in the striatum extends into the early neonatal period under normal physiological conditions in the rat brain, with low but stable contributions of striatal interneurons during this time-period. Using retroviral labeling, we further show how MSNs born neonatally, correctly acquire their axonal targets in the globus pallidus and midbrain. These data provide evidence of latent MSN development in the neonatal striatum post- embryogenesis and as such, these new born cells provide promising targets for gene therapy to promote endogenous self-repair during neonatal striatal injury such as in cerebral palsy. Based on this, we are developing a novel hypoxia-independent neonatal stroke model in order to compare our results with striatal neurogenesis in a damaged brain which will give further insight into whether MSN production is enhanced or inhibited due to striatal damage.
64 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
ABSTRACTS – POSTER PRESENTATIONS
P1. Barbuti Generating patient-derived Parkinsonian iPS cell lines, their differentiation to midbrain dopaminergic neurons and susceptibility to neurotoxic insults Peter A. Barbuti 1, Jennifer L. Badger 1, Lucy A. Crompton 1, Alan L. Whone 2, James B. Uney 1 and Maeve A. Caldwell 1 1University of Bristol, and 2Department of Neurology, Frenchay Hospital, Bristol, UK. (Email: [email protected]). Parkinson’s disease (PD) is neurodegenerative disease clinically characterised by the loss of A9 dopaminergic neurons in the substantia nigra pars compacta (SNc) of the midbrain. Using patient-derived stem cells we aim to model the disease by recapitulating the neurons lost in PD and investigate their susceptibility to neurotoxic insult. Dermal fibroblasts from idiopathic and genetic PD patients were transduced with lentiviruses to generate induced pluripotent stem (iPS) cell lines. We have developed a robust protocol for the generation of dopaminergic neurons of the SNc and have characterised these neurons from lines generated for the markers of SNc and their dopamine release. We have then subjected these neurons to neurotoxic insults to model PD in-vitro and are currently looking at ways to protect these de-novo neurons from toxicity and prevent their degeneration. Acknowledgement: This work was funded by Parkinson’s Disease UK
[For poster presentation, poster board 13 on Wednesday 4th September 2013]
65 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P2. Breger Understanding rejection of allogeneic and xenogeneic dopaminergic cell transplants. Ludivine S Breger 1,2, Stephen B Dunnett 2 and Emma L Lane 1 1 School of Pharmacy and Pharmaceutical Sciences, and 2 Brain Repair Group, School of Biosciences, Cardiff University, Wales, UK. (Email: [email protected]). A restorative approach for Parkinson’s disease (PD) is the transplantation of foetal ventral mesencephalon (VM). Post-mortem studies of patients treated in previous clinical trials have revealed the presence of infiltrated immune cells [1], which may result from a lack of immune compatibility between the donor cells and the host. The impact this may have on the functional outcome of cell therapy for PD has yet to be determined. To address this question, it is necessary to establish a controlled model of rejection so this work compared the rejection of allograft and xenograft transplants in rat hosts. 6-OHDA unilaterally lesioned Sprague Dawley received intrastriatal VM transplant derived from embryos of CD1 mice (xenograft) or Wistar rats (allograft). To establish the time course of rejection, xenografted animals received immunosuppressive treatment (cycloA) for different durations, while rejection of the allograft was obtained by peripheral injections of spleen cells [2]. Rotational behavior in response to amphetamine was used as a behavioural assessment of graft survival alongside immunohistochemical analysis. The immune response, determined by infiltration of leukocytes, appears within the second week of withdrawal of immunosuppression, although no significant cell loss was observed before the 3rd week. Regarding the allograft model, the use of different time points for spleen cells injections induced different degrees of rejection, from 23% to 96% grafted cell loss, 4 weeks post-graft, therefore creating a more controllable model than the xenograft model. 1. Kordower JH et al. Cell Transplantation, 1997; 6: 213-219. 2. Soderstrom KE et al. Neurobiology of Disease, 2008; 32: 229-242.
[For poster presentation, poster board 15 on Wednesday 4th September 2013]
66 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P3. Bubak A potential compensatory role for endogenous striatal tyrosine hydroxylase- positive neurons in a non-human primate model of Parkinson’s disease Andrew N. Bubak 1, D. Eugene Redmond, Jr 3., John D. Elsworth 4, Robert H. Roth 4, Timothy J. Collier 5, Kimberly B. Bjugstad 2, Barbara C. Blanchard 2, and John R. Sladek, Jr. 2 1 Neuroscience, 2 Neurology and Pediatrics, University of Colorado-Denver, Anschutz Medical Campus, 3 Psychiatry and Neurosurgery, 4 Pharmacology, Yale University School of Medicine and 5 Center of Excellence in Parkinson’s Disease Research, Michigan State University, USA. (Email: [email protected]). The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine) selectively destroys dopaminergic (DA) neurons in the nigrostriatal pathway while importantly sparing other DA systems, serving as a significant tool in Parkinson’s disease (PD) research. Extensive studies in our laboratories have shown reversal of MPTP induced PD symptoms following striatal grafts of fetal ventral mesencephalic DA neurons in the African Green monkey. Additionally, our and other studies have reported an upregulation of endogenous tyrosine hydroxylase (TH) positive neurons in the striatum following MPTP lesions (~140% increase). The aim of the current research is to investigate the fate of this endogenous population in MPTP treated monkeys following fetal cell grafts. Preliminary results indicate a return to control levels for the TH-positive cells following successful transplantation, while animals whose donor cell grafts failed to contain DA neurons retained the elevated levels. If these cells represent a compensatory mechanism in an attempt to replenish DA in the striatum, then the ability to influence this population could prove beneficial in developing new non-invasive therapeutic treatments. Current research investigating the origin of these cells and their relationship to symptom severity is ongoing. Supported by an Academic Enrichment Grant from the University of Colorado School of Medicine, The Axion Research Foundation, and 5PO1NS044281.
[For poster presentation, poster board 1 on Wednesday 4th September 2013]
67 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P4. Choompoo Human Induced Pluripotent Stem (iPS) Cells for Cell Replacement Therapy in Huntington's disease. Choompoo N, Vinh NN, Kelly CM, and Rosser AE BRG, School of Biosciences, Cardiff University, UK. (Email: [email protected]). Huntington’s disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin gene (HTT). The extended CAG repeat ultimately leads to loss of medium spiny neurons (MSNs) in the striatum of the HD brain. Cell replacement therapy using primary human fetal tissue has shown ‘proof of principle’ as a strategy to treat this genetically inherited disease1. However, alternative cell sources need to be identified to overcome the ethical and logistical issues that are associated with using human fetuses. IPS cells were first introduced by Yamanaka in 2006 by direct reprogramming of fibroblasts to ES- like cells by using four defined factors (Oct4, Sox2, Klf4, c-Myc)2. Here we attempt to generate safety iPS cells by introduce reprogramming factors using piggyBac Transposon3 transduction system to human fetal fibroblasts and fetal neural stem cells which theoretically have the potential to be more readily reprogrammed and are genetically unrelated to the host. The establishing iPS cell line were present the similarities to human embryonic stem (ES) cells in morphology, surface antigen, and proliferation. 1 Kelly, M.C. et al. Medium spiny neurons for transplantation in Huntington’s disease. Biochem. Soc. Trans. (2009) 37, 323-328. 2 Takahashi K., Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell (2007) ;131:861-872. 3 Woltjen K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature (2009) 458:766-770.
[For poster presentation, poster board 27 on Thursday 5th September 2013]
68 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P5. Di Santo Differential neuroprotective capacity of Endothelial Progenitor Cells-derived factors Stefano Di Santo, Stefanie Seiler, Hans R. Widmer Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Switzerland. (Email: [email protected]). Stem and progenitor cells release a wide array of trophic factors, cytokines and extra- cellular matrix molecules. The present study aimed at investigating whether endothelial progenitor cells (EPC) may support neuronal functions and survival by means of paracrine factors. EPC isolated from peripheral blood of healthy human donors were cultured in hypoxic conditions to stimulate secretion of growth factors. Primary cultures from fetal rat embryonic (E14) ganglionic eminence (GE) and ventral mesencephalon (VM) were treated with EPC derived conditioned medium (EPC-CM). Incubation of cultures with EPC-CM resulted in a significant increase in TH-ir cell densities in VM as well as GABA-ir cell densities in the GE cultures, respectively. Interestingly, treatment of cultures with EPC-CM resulted in a substantial increase in number of microglial cells. Notably, EPC-CM displayed neuroprotection against MPP+ toxicity in VM cultures whereas it was not effective against 3NP toxicity. The effect of EPC-CM on TH-ir cells persisted upon treatment with Ara-C conducted in order to limit microglia expansion. Our findings identified EPC-CM as a powerful tool to promote viability and/or different- iation of neuronal cells. EPC-CM constituents might represent a new strategy to support neuronal repair. Supported by the Swiss National Science Foundation and the Hanela Foundation
[For poster presentation, poster board 8 on Wednesday 4th September 2013]
69 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P6. Evans Characterisation of FoxP1 in the striatum Evans AE 1,2, Taylor MV 2 and Rosser AE 1,2 1 Brain Repair Group and 2 Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. (Email: [email protected]). Medium Spiny Neurons (MSNs) constitute >90% of the projection neurons in the striatum and are lost in Huntington’s disease (HD). A screen looking at gene expression changes in the developing striatum of mice (E12-E16) showed FoxP1 to be the most up-regulated gene over this period. FoxP1 is also expressed in the adult striatum and has the potential to be a marker of both developing and mature MSNs (Tamura et al., 2003). Understanding the regulation of striatal development, in particular, the differentiation of MSNs is the key to finding strategies to ‘direct’ the differentiation of such cells from pluripotent stem cells. This in turn is crucial for generating genuine striatal cells for cell therapy in conditions such as HD. To date the function of Foxp1 in the brain is unknown. Homozygous FOXP1 knock-outs (FoxP1-/-) in mice are embryonically lethal from ~E15 due to cardiac defects (Wang et al., 2004). However, one can analyse the embryos before the onset of lethality. Using several techniques we have attempted to understand what role FoxP1 has in MSN differentiation. Results show that there is a decrease in the number of DARPP-32 expressing neurons when FoxP1 is absent. In addition, ongoing microarray analysis will highlight differences at a genomic level, between the FoxP1-/- nulls and WTs in the striatum at E14.
[For poster presentation, poster board 28 on Thursday 5th September 2013]
70 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P7. Fjodorova Birth dating of dopamine neuron subtypes in ventral mesencephalon grafts in a rat model of Parkinson’s disease Fjodorova M, Torres EM and Dunnett SB Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. (Email: [email protected]). Using co-expression of tyrosine hydroxylase (TH) with GIRK2 and Calbindin1 to identify A9 and A10 dopamine neuron subtypes, respectively, we have previously shown that 80% of TH-positive neurons in the grafts derived from E12 and E14 rat ventral mesencephalon were of A9 subtype. The site of transplantation was found to have a significant effect on the survival of dopamine neurons and the distribution of the two phenotypes across the periphery and the centre of the graft. It is unclear however, whether this is due to different survival levels or differentiation of dopamine neuron precursors after transplantation. Here we used BrDU labelling to birth date E12 and E14 dopamine neurons after transplantation into the striatum. Preliminary results show strong BrDU labelling and its co-localisation of with TH in the grafts. Further analysis will reveal how the on-going in vivo proliferation of dopamine neuron precursors contributes to the survival of two dopamine neuron phenotypes. The evidence suggests that younger dopamine neuron precursors are better suited for the cell transplantation therapy in PD as they are able to differentiate in vivo and yield higher dopamine neuron survival. Acknowledgement. This work was funded by the Wellcome Trust. Reference. Thompson L, Journal of Neuroscience, 2005; 25: 6467-77.
[For poster presentation, poster board 2 on Wednesday 4th September 2013]
71 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P8. Fricker Vitamin D3 promotes dopamine neuron survival through upregulation of GDNF Rowan P. Orme, Manminder Bhangal and Rosemary A. Fricker School of Medicine & ISTM, Keele University, UK. (Email: [email protected]). Vitamins play a key role in brain development and neuronal survival. In previous work using an iTRAQ proteomics technique and immunohistochemistry we identified vitamin D3 receptor expression during peak neurogenesis of dopamine neurons in the ventral midbrain. In this study we applied the active metabolite of vitamin D3, calcitriol, to cultures of embryonic day 12 ventral mesencephalon neurons to investigate its role in neuronal differentiation and survival. Calcitriol enhanced the total number of tyrosine hydroxylase- positive dopamine neurons in a dose dependent manner, up-regulating GDNF, and proffering neuroprotection rather than generating new dopamine neurons. Blocking GDNF signalling reversed calcitriol’s positive effect on enhancing the number of dopamine neurons. We then treated E12 ventral mesencephalic cell suspensions with vitamin D3 - either as calcitriol to the transplant suspension or vitamin D3 delivered orally – prior to transplantation in 6-OHDA lesioned rats. Although all grafts reversed amphetamine- induced rotation to a similar degree, vitamin D3-treated grafts gave earlier recovery in the cylinder test compared with control transplants. Transplant histology to assess vitamin D3’s effects on dopamine neuron survival and graft-host innervation will be presented. Acknowledgement: This work was funded by Parkinson’s UK and Keele Medical School.
[For poster presentation, poster board 16 on Wednesday 4th September 2013]
72 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P9. Geater Direct programming of neural stem cells into medium spiny neurones by transcription factor transfection Charlie R. Geater, Paul J. Kemp and Nicholas D. Allen School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX. UK (Email: [email protected]) Huntington’s disease is a neurodegenerative disease with genetic causality. The genetic mutation causes selective cell death of medium spiny neurons (MSN) which reside in the striatum. Currently there is no cure available and treatment is severely limited, as a result the patient death occurs within 20 years from diagnosis. In order to fully understand the disease an accurate disease model needs to be available. Current animal models only recapitulate certain aspects of disease phenotype, therefore other avenues need to be explored. The advent of induced pluripotent stem cell (iPSC) technology means disease specific iPS cell lines can be generated from affected patients. However, current methods of stem cell differentiation into medium spiny neurones are not efficient and rarely reproducible. Multi-cistronic plasmids have been constructed to enable expression of multiple transcription factors important in post-mitotic MSN development. Expression of the plasmids was used to optimise the MSN differentiation of neural pre-cursors derived from control iPSCs. The level of DARPP32 expression, a marker of MSNs, was monitored throughout differentiation. Future work will look to further characterise these neurons by electrophysiology and expression of other medium spiny neuronal markers and utilising patient-derived iPS to form a disease model of Huntington’s disease. Acknowledgements: Funded by CHDI.
[For poster presentation, poster board 26 on Thursday 5th September 2013]
73 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P10. Gonzalez-Cordero Effective transplantation of photoreceptors derived from three-dimensional cultures of embryonic stem cells Anai Gonzalez-Cordero, Emma West, Rachael Pearson, Jane Sowden and Robin R Ali Institute of Ophthalmology, University College London, 11-13 Bath Street, London EC1V 9EL, UK. (Email: [email protected]). Irreversible blindness caused by loss of photoreceptors may be amenable to cell therapy. We have previously demonstrated retinal repair1 and restoration of vision through transplantation of photoreceptor precursors obtained from postnatal retinas into visually impaired adult mice2,3. Considerable progress has been made in differentiating embryonic stem cells (ESCs) in vitro toward photoreceptor lineages4-6. However, the capability of ESC-derived photoreceptors to integrate after transplantation has not been demonstrated unequivocally. In order to isolate photoreceptor precursors fit for transplantation, we have adapted a recently reported three-dimensional (3D) differentiation protocol that generates neuroretina from mouse ESCs6. We have now shown for the first time that ESCs can provide a source of photoreceptors for retinal cell transplantation7. 1. Maclaren, R. E. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203–207 (2006). 2. Pearson, R. A. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012). 3. Barber, A. C. et al. Repair of the degenerate retina by photoreceptor transplantation. PNAS 110, 354–359 (2013). 4. Lamba, D. A., Karl, M. O., Ware, C. B. & Reh, T. A. Efficient generation of retinal progenitor cells from human embryonic stem cells. PNAS 1–6 (2006). 5. Osakada, F. et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nature Biotechnology 26, 215–224 (2008). 6. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011). 7 Gonzalez-Cordero et al. Nature Biotechnology in press (2013) Photoreceptor precursors derived from three- dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina
[For poster presentation, poster board 41 on Thursday 5th September 2013]
74 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P11. Griffin The influence of nicotinamide on directed differentiation of neurons from embryonic stem cells in vitro Síle M. Griffin, Mark R. Pickard, Rowan P. Orme, Clive P. Hawkins and Rosemary A. Fricker Institute for Science and Technology in Medicine, Keele University, Staffordshire, UK (Email: [email protected]) Factors controlling proliferation and differentiation are crucial towards advancement of neural cell-based experimental neurodegenerative therapies. In this regard, nicotinamide has been shown to function in neural cell fate determination, enhance neuralization and influence DNA repair and apoptosis. This study investigated whether nicotinamide could direct the differentiation of mouse embryonic stem cells (mESCs), cultured as monolayers, into neurons. 5mM and 10mM nicotinamide added at days 0-7 and 7-14 significantly increased β-III tubulin positive neuronal populations, concomitantly decreasing the total number of cells in culture measured by quantification of 4’,6-diamidino-2-phenylindole (DAPI) positive cells. Interestingly, nicotinamide had a more significant effect on neuronal differentiation at day 0-7. Current work is focusing on elucidating the mechanism mediating neural specification by nicotinamide, i.e. induction of cell-cycle exit and/or selective apoptosis in non-neural populations. Preliminary data indicates a reduction in the proportion of proliferating cells in nicotinamide-treated cultures, suggesting that nicotinamide may enhance cell-cycle exit thereby promoting neuronal differentiation. We are currently investigating the effect of nicotinamide on the process of neural induction and whether it influences neuronal subtypes generated in vitro. Future work will focus on evaluating the effect of nicotinamide on the differentiation of midbrain dopamine neurons; towards a therapy for Parkinson’s disease.
[For poster presentation, poster board 4 on Wednesday 4th September 2013]
75 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P12. Griffiths Brain endogenous Liver X Receptor ligands selectively promote midbrain neurogenesis Spyridon Theofilopoulos 1, Yuqin Wang 2, William J. Griffiths 2 and Ernest Arenas 1 1 Karolinska Institutet, Stockholm, Sweden, and 2 Swansea University, UK (Email: [email protected]). Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we employed LC-MS and functional assays to identify cholic acid as a novel Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development, in an Lxr-dependent manner, in zebrafish in vivo. Intriguingly, each ligand selectively regulated the development of distinct midbrain neuronal populations. While cholic acid increased survival and neurogenesis of Brn3a+ Red Nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell-type specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of ES cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement/regenerative therapies for Parkinson’s disease [1]. [1]. Theofilopoulos S, et al. Nat Chem Biol. 2013 Feb;9(2):126-33. Acknowledgement. This work was funded by BBSRC and the Swedish Research Council.
[For poster presentation, poster board 21 on Wednesday 4th September 2013]
76 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P13. Handreck Safety study on cyclosporine A in epilepsy models Annelie Handreck 1,2, Eva M. Mall 1, Deborah A. Elger 1, Laura Gey 1,2 and Manuela Gernert 1,2 1 Dept of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover; 2 Center for Systems Neuroscience, Hannover, Germany. (Email: [email protected]). Neural transplantation of inhibitory cells into seizure initiating or propagating brain regions is one promising approach to treat pharmacoresistant epilepsies. Depending on the grafted cell type (e.g. xenotransplantation), immunosuppression is necessary to prevent graft rejection, thereby enabling long-lasting anticonvulsant effects of the graft. We therefore investigated the effects of daily treatment (15 days) with different preparations of the commonly used immunosuppressive drug cyclosporine A (CsA) (pure substance or ready-to-use-drug Sandimmun®, Novartis), doses (5 or 10 mg/kg), and application routes (i.p. vs. s.c.) on acute and chronic seizure thresholds in rats. Additionally, CsA whole blood levels were analyzed and behavioral tests were conducted to detect side effects. The data did not reveal acute and only subtle chronic effects of immunosuppression with either pure CsA or Sandimmun® on seizure thresholds. The resorption of i.p. applied CsA from Sandimmun® exceeded the resorption from the pure CsA preparation. Unwanted side effects included transient gastrointestinal problems. Our data indicate that immuno- suppression with 10 mg/kg Sandimmun® i.p. rather than pure CsA is a safe and feasible option for use in neural transplantation experiments in epilepsy models. Acknowledgements: Supported by the DFG (Ge1103/7-2). AH is supported by the Prof. Dr. Peter and Jytte Wolf Foundation for Epilepsy.
[For poster presentation, poster board 31 on Thursday 5th September 2013]
77 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P14. Harrison Are transplant-induced improvements in cognitive performance in the rat lesion model of Huntington’s Disease dependent on frontal-striatal circuit reconnection? Harrison DJ, Brooks SP and Dunnett SB Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. (Email: [email protected]). Frontal-type executive function, demonstrated in rats using a delayed alternation (DA) task, is disrupted when continuity of both cortico-striatal loops of the associated neural circuitry are interrupted. Bilateral grafts of embryonic whole ganglionic eminences (WGEs) restore function in the DA task in bilateral striatally lesioned rats, with transplanted tissue integrating with the host brain. However, it has not been definitively shown that improvement in cognitive performance is due to physical reconstruction of neural circuitry or if grafted tissue simply exhibits other beneficial influences on the host brain, for example by releasing donor derived growth factors. Therefore, in the present study, we aim to determine the role of circuit reconstruction in the attenuation of cognitive deficits. This is to be assessed by training rats on the operant DA task and evaluating performance following bilateral striatal lesions, unilateral striatal transplantation of WGE, and ipsilateral or contralateral surgical disconnection of the prefrontal cortico-striatal circuitry. We hypothesise that unilateral grafts should provide effective alleviation of the bilateral striatal lesion deficit, and that contralateral knife cuts will preserve prefrontal cortical afferents to the grafted striatum thus maintaining cognitive performance, whereas ipsilateral disconnection of the graft will reinstate the deficit. The data presented represents the current status of the study. This work is supported by the MRC.
[For poster presentation, poster board 24 on Thursday 5th September 2013]
78 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P15. Heuer Optogenetic manipulation of hESCs and in vivo measurement of dopamine release Andreas Heuer, Shane Grealish, Agnete Kirkeby, Martin Lundblad and Malin Parmar Developmental Neurobiology, Parmar Group, Lund University, Lund, Sweden. (Email: [email protected]). Human embryonic stem cells (hESCs) are a possible alternative to primary fetal tissue for the transplantation of dopamine neurons into patients with Parkinson’s disease (PD). We aim to investigate the contribution of engrafted hESC-derived mesencephalic dopamine (mesDA) neurons on functional improvements in a rat model of PD. In this study we use Channelrhodpsin (ChR2) allowing us to manipulate cell activity and release DA with light pulse stimulation, at a high temporal resolution. By transducing hESCs with an LV-vector to express ChR2 under the synapsin-1 promoter (Syn), transplanted cells will express the construct in neurons. Here we engrafted one group of 6-hydroxydopamine lesioned rats with H9-hESC-Syn-ChR2 cells that were patterned towards a mesDA phenotype whilst having a lesioned group serving as control. We will assess cell survival and dopamine release of transplanted cells via amphetamine-induced rotations as well as using in vivo amperometry in conjunction with optogenetic stimulation, in order to manipulate neural activity. At the conference we will present the first findings of this study. It is hoped the results from this study will provide insight into the neurochemical events that underpin graft-mediated DA- release/functional recovery in rat models of PD.
[For poster presentation, poster board 12 on Wednesday 4th September 2013]
79 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P16. Hoffmann Influence of transcranial direct current stimulation on the survival, migration and integration of dopaminergic cell transplants in a rat model of Parkinson´s disease: a histological and behavioral analysis Fritsch, B 1; Hoffmann, N 1,2; Furlanetti, L 2; García, J 1,2; Döbrössy, MD 2; Winkler, C 1 1 Department of Neurology, University Hospital Freiburg, Germany; 2 Laboratory of Stereotaxy and Interventional Neuroscience, University Hospital Freiburg, Germany. (*Email: [email protected]) Introduction: Parkinson´s disease (PD) is a challenging disease, which leads to progressive and disabling deterioration of motor and cognitive skills. Transcranial direct current stimulation (tDCS) is a non-invasive technique that presents modulatory effects on cognitive functions and motor behavior. Regenerative approaches are under research to restitute dopaminergic neurotransmission and offer a more extensive and long lasting effect. In this study we analyzed the effect of tDCS on the survival, migration and integration of dopaminergic cell transplants. Method: Rats received unilateral dopamine-denervating lesions using 6- hydroxydopamine. Afterwards, they were randomly assigned into three groups (Anodal- Stim, Cathodal-Stim and Sham-Stim) according to values in amphetamine-induced rotation. All groups were transplanted with E14 GFP+ ventral mesencephalic (VM) cells into the ipsilateral striatum. tDCS was started right after transplantation and performed for 20 minutes daily, during 2 weeks. Amphetamine-induced rotation and cylinder test were performed pre transplantation and 5 weeks after transplantation, respectively. Rats were perfused 5 weeks after transplantation and histological analysis was performed. Results: Survival of transplanted VM cells in the striatum was increased by approximately 50% in the anodally stimulated group as compared to sham and cathodal groups, and optical fiber density was increased in the anodal tDCS-group. All groups improved their scores in amphetamine-induced rotation, but there were not improvements in the cylinder test at this early time-point after grafting. Conclusion: Transcranial direct current stimulation improved graft survival and fiber outgrowth of intrastriatal dopamine grafts in a rat PD model. Further studies are ongoing to confirm and extend these findings.
[For poster presentation, poster board 5 on Wednesday 4th September 2013]
80 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P17. Jensen Trefoil Factor 1 in the nigrostriatal system of 6-hydroxydopamine-lesioned rats Pia Jensen 1, Michel Heimberg 2, Angelique D. Ducray 2, Hans R. Widmer 2 & Morten Meyer 1 1Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; and 2Department of Neurosurgery, University of Bern, Switzerland. (Email: [email protected]). Trefoil factor 1 (TFF1) belongs to a family of secreted peptides mainly expressed in the gastrointestinal tract. TFF1 has also been suggested as a neuropeptide, but not much is known about its expression and function in the CNS. We investigated the expression of TFF1 in control and 6-hydroxydopamine (6-OHDA)- lesioned rats. In the unlesioned ventral mesencephalon, TFF1-immunoreactive (-ir) cells were mainly found in substantia nigra pars compacta (SNc) and in the ventral tegmental area. While around 90% of the TFF1-ir cells in SNc co-expressed tyrosine hydroxylase (TH), only a subpopulation of TH-ir neurons expressed TFF1. Some TFF1-ir cells in SNc co- expressed calbindin or calretinin, and nearly all were NeuN-ir while there was no co- localization with the astroglial marker GFAP. A few TFF1-ir cells were also found in the striatum, and their numbers significantly increased after 6-OHDA lesion. Intrastriatal injection of Fluorogold resulted in retrograde labeling of several TFF1-ir cells in the SNc showing that these cells were projection neurons. This was also reflected by unilateral loss of TFF1-ir cells in the SNc of 6-OHDA-lesioned rats. Our findings demonstrate that distinct subpopulations of midbrain dopaminergic neurons express TFF1 and that this expression pattern is altered in a rat model of Parkinson’s disease.
[For poster presentation, poster board 6 on Wednesday 4th September 2013]
81 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P18. Kaindlstorfer Comparison of L-Dopa response patterns of different stages of MSA-P in a double lesion rat model Christine Kaindlstorfer 1, Joanna García 2, Nadia Stefanova 1, Werner Poewe 1, Christian Winkler 3, Mate Döbrössy 2 and Gregor Wenning 1 1 Neurology, Medical University, Innsbruck, Austria; 2 Molecular Neurosurgery, Medical University, Freiburg, Germany; 3 Neurology, Medical University, Freiburg, Germany. (Email: [email protected]). The objective of this study was to identify the striatal sub-region and QA dosage replicating L-Dopa failure in a partial double lesion rat model of MSA-P. Three experimental groups were investigated: (1) PD group receiving 6-OHDA lesion, (2) MSA-P mild (3) MSA-P severe group receiving 6-OHDA and QA lesion. Following 6-OHDA lesion all groups showed significant behavioral deficits in cylinder and stepping test, without further deterioration after QA lesion except MSA-severe group with significant impairment in stepping test. Amphetamine induced rotation resulted in ipsilateral rotation of PD and MSA groups, whereas apomorphine induced contralateral rotation in PD and ipsilateral rotation in MSA groups. All groups revealed a significant L-Dopa response in cylinder and stepping test after 6-OHDA lesion that was significantly reduced in both MSA groups following the subsequent QA lesion, with a trend of MSA-P severe group being most resistant to L-Dopa. In conclusion, the current study describes the unique motor behavior and L-Dopa response patterns in association to the location and the dosage of the QA lesion of double lesioned animals compared to single 6-OHDA lesioned animals. Both QA lesion approaches in MSA-mild and MSA-severe groups led to a reduction of L-Dopa responsiveness, whereas the higher dose of QA showed the greatest reduction of such. This refined model of MSA-P replicating L-Dopa failure is highly suitable for future grafting studies with the rational of restoring L-Dopa responsiveness.
[For poster presentation, poster board 29 on Thursday 5th September 2013]
82 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P19. Kauhausen Cell intrinsic and extrinsic factors contribute to enhance neural circuit reconstruction following transplantation in Parkinsonian mice
Jessica Kauhausen,, Lachlan Thompson and Clare Parish Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia. (Email: [email protected]). Homotopic grafting into the SNpc is capable of restoring the nigrostriatal pathway and forming appropriate connections with the striatum, but the extent of striatal reinnervation remains substantially less than can be achieved with ectopic placement. The aim of this investigation was to determine what effect donor age and virally delivered glial derived neurotrophic factor (GDNF) over-expression had on the survival, growth and integration of homotopic grafts placed into 6OHDA mouse model of Parkinson’s disease. Younger donor tissue (E10) showed to be capable of generating larger grafts with more axonal growth compared to grafts generated from the more conventional E12 donor VM. With the addition of GDNF, fiber growth and striatal innervation was further enhanced in both older and younger donor tissue. Immunohistochemical staining revealed that younger donor grafts treated with GDNF resulted in an increased number and proportion of A9 DA neurons. Behavioural testing confirmed that younger donor grafts provided a significant improvement in motor behavior with GDNF overexpression only affecting E12 donor tissue. These findings could have significant implications for the future development of cell replacement therapy for the treatment of Parkinson’s disease.
[For poster presentation, poster board 17 on Wednesday 4th September 2013]
83 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P20. Mattis Neonatal immune-tolerance in mice does not prevent xenograft rejection; a comprehensive analysis using in vivo luciferase tracking Virginia B. Mattis 1, Dustin R. Wakeman 2, Colton Tom 1, Hemraj B. Dodiya 2, Jack Reidling 3, Andrew Tran 3, Ksenija Bernau 4, Loren Ornelas 1, Anais Sahabian 1, Dhruv Sareen 1, Leslie M. Thompson 3, Jeffrey H. Kordower 2 and Clive N. Svendsen 1 1Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California; 2Rush University, Chicago, Illinois; 3University of California-Irvine, Irvine, California; and 4Unviersity of Wisconsin-Madison, Madison, Wisconsin. (Email: [email protected]). While in vitro iPSC models are proving extremely informative, an in vivo “humanized” chimeric animal model of disease via transplantation of diseased human iPSC-derived cells may prove ideal for therapeutic screening and mechanistic discovery. One of the major challenges for the field is appropriate immune suppression in these xenograft models as it is often ineffective or cost-prohibitive for long term studies, and has also been shown to ameliorate neurological diseases (Rosenstock et al. Neurochem Int. 2011), complicating experimental results. With the promise of transplantation for neurodegenerative diseases, there also is the need for non-invasive in vivo tracking. In the current collaborative study we used a range of techniques and cells to establish tolerance of the neonatal and adult rodent brain to neural xenografts. We show that in contrast to rats, mouse neonates are sensitive to human neural xenografts (from iPSCs, ESCs or fetal tissues). In three mouse strains, prior sensitization had no effect on the severe rejection of the cells. Luciferase imaging was shown to be a powerful predictor of graft survival in the striatum. Together these studies show that neonatal mice reject human cells, and that immune tolerance techniques are not sufficient to prevent rejection in adult mice.
[For poster presentation, poster board 19 on Wednesday 4th September 2013]
84 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P21. Metcalfe Human fetal dopaminergic precursor cell transplantation: LIF-nanotherapy to promote graft survival. Metcalfe SM 1, Zhao JW 1, Tyers P 1, He X 1, Fahmy TM 2, Barker RA 1 1 University of Cambridge, Brain Repair Centre, UK; 2 Yale University, Biomedical Engineering, USA. (Email: [email protected]).
LIF (Leukaemia Inhibitory Factor) is both a neuropoietic and a tolerogenic cytokine. Thus LIF represents a promising candidate for treating neural cell grafts to promote their survival whilst simultaneously suppressing any immune reactivity against the graft. Since in vivo use of LIF is hindered by its rapid degradation and excretion, we have prepared a nano-particulate formulation of LIF intermixed with PGLA, a biocompatible, biodegradable polymer similar to that used in soluble sutures. These "LIF-nano" are decorated with avidin allowing attachment of biotinylated anti-Thy1 to bind the particles to neural precursor cells prior to grafting LIF also plays a role in supporting neural stem and precursor cells, and may provide dual therapeutic benefits for cell transplantation in Parkinson's Disease (PD). The TransEuro Project (http://www.transeuro.org.uk) is currently evaluating grafts of human fetal ventral mesencephalon (hfVM, rich in precursor dopaminergic cells) in treatment of PD. Working in parallel, we have shown that, ex vivo, LIF-nano-treated hfVM yield over 3-fold more dopaminergic cells compared to empty-nano controls. Similarly, in vivo, intra-striatal hfVM grafts in nude rats show major beneficial effects of LIF-nano therapy, both in graft survival and in dopaminergic cell maturation. This has major implications for clinical transplantation, reducing numbers of cells required for therapeutic effect. This work is supported by an NIHR i4i Grant.
[For poster presentation, poster board 18 on Wednesday 4th September 2013]
85 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P22. Modo Simultaneous in vivo monitoring of transplanted cells and biomaterials by magnetic resonance imaging Wen Ling 1*, Francesca Nicholls 1,2*, Daniela delli Castelli 3, Christopher J. Medberry 1, Tao Jin 1, Seongi Kim 1, Stephen F. Badylak 1, Silvio Aime 3, Michel Modo 1 * both authors contributed equally; 1 University of Pittsburgh, USA; 2 King’s College London, UK, 3 University of Turin, Italy. (Email: [email protected]). Non-invasive in vivo monitoring of regenerative medicine approaches for tissue and organ reconstruction will be an important technological development to ensure the safety and efficacy of such strategies. However, the involvement of multiple types of cells as well as biomaterials complicates in vivo monitoring that is dependent on a single contrast mechanism. Herein we explored the use of chemical exchange saturation transfer (CEST) to specifically visualize different elements (multiple cell types and biomaterials) used for an in situ regenerative medicine approach for the treatment of the stroke-damaged brain. Specifically, neural stem cells and endothelial cells were labelled using paramagnetic CEST (PARA-CEST) agents, whereas an extracellular matrix (ECM)-derived bioscaffold was detected using diamagnetic CEST (DIA-CEST). Intracellular incorporation of PARA-CEST agents (Eu-HPDO3A and Yb-HPDO3A) was titrated to exert minimal biological effects on the cells while ensuring sufficient levels were achieved to afford detection in vitro and in vivo. Z spectra were acquired for labelled cells as well as ECM bioscaffold prior to ex vivo and in vivo imaging in a rat model of stroke. Although significant challenges remain, these results provide proof-of-principle that non-invasive imaging of tissue engineering in the brain is feasible. Acknowledgements: Funded by the European Union (201842- ENCITE), the Department of Health of Pennsylvania (4100061184), and the Department of Radiology, University of Pittsburgh, USA.
[For poster presentation, poster board 40 on Thursday 5th September 2013]
86 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P23. Özer EGFP-Flag transfected rat progenitor cells display electrophysiological properties of integrated functional dopaminergic (DA) neurons similar to genetically labelled DA-neurons in vitro and intrastriatally xenografted DA- neurons in a rat model of Parkinson’s disease Özer Meltem 1, Rumpel Regina 1, Fischer Martin 2, Donert Malte 1, Klein Alexander 1, Wesemann Maike 1, Ratzka Andreas 1, Effenberg Anna 1, Fahlke Christoph 3 and Grothe Claudia 1 1 Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany; 2 Institute of Neurophysiology, Hannover Medical School, Hannover, Germany; 3 Institute of Complex Systems, Zelluläre Biophysik, FZ Jülich, Jülich, Germany. (Email: [email protected]). Whole cell patch clamp studies of intrastriatally grafted EGFP-Flag transfected ventral mesencephalic (VM) progenitor cells in brain slices displayed 2 types of neurons showing dopaminergic (Da)-like properties marked by the hyperpolarisation activated anomalous rectification. Type-1 neurons display hyperpolarisation activated rectification followed by delayed, single action potentials, and pacemaker activity. Type-2 neurons attract attention by distinct spontaneous bursting and bursting after hyperpolarisation. To clarify whether one or both Da-like neurons are actually dopaminergic, fetal VM progenitor cells of a transgenic TH-GFP mouse were used to visualise Da neurons, after grafting in a 6-OHDA- rat model, directly due to expression of fluorescent labelled tyrosine hydroxylase. These TH-GFP mice-derived Da-neurons we previously electrophysiologically characterized in vitro. Since 6-OHDA lesion induces reduction in the ability to use the contralateral paw, an evaluation of motor skills by a staircase test can monitor functional integration of the grafts. This is an alternative behavioural test to drug-induced rotation, which might influence the electrophysiological properties in situ. Overall, patch clamp analysis of genetically labelled Da-neurons together with behavioural studies facilitate the direct investigation of functional properties of Da neurons in vitro and after intrastriatal grafting.
[For poster presentation, poster board 10 on Wednesday 4th September 2013]
87 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P24. Pabón Histopathological effects of varying the impact trajectories in experimental model of TBI Mibel M. Pabón, Naoki Tajiri, Kazutaka Shinozuka, Sandra Acosta, Hiroto Ishikawa, Diana Hernandez-Ontiveroz, Julie Vasconcellos, Travis Dailey, Christopher Metcalf, Meaghan Staples, Cyrus Tamboli, Yuji Kaneko and Cesar V. Borlongan Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, Univ. of South Florida, Tampa, FL, USA. (Email: [email protected]) About 1.7 million people sustain TBI annually leading to significant disability and death around the world. Most of the TBI animal models focus on a single 90-degree trajectory affecting a specific brain area; but TBI patients do not always display injury to the same brain regions. We examined histopathological effects at 3 days after controlled cortical impact (CCI) model in adult Sprague-Dawley rats. We hypothesized that different impact trajectories would produce varying levels of brain damage. CCI manipulations included: 1. conventional TBI targeting frontal cortex, 2. farthest right angle (FRA) and 3. closest right angle (CRA) both also targeting frontal cortex, 4. olfactory bulb (OB), and 5. cerebellar (CB) injury. Data showed typical cell loss in M1 cortical region in the conventional TBI, FRA, and CRA groups using H&E staining and Cavalieri method. No significant cell death was detected in M1 region of animals that received OB or CB injury. Comparable CA3 hippocampal cell loss in both hemispheres was noted across TBI groups. Increased expression of activated microglial marker OX-6 in M1 region accompanied conventional TBI, FRA, and CRA suggesting a critical inflammatory role. These results provide a closer clinical approximation of varying TBI histopathological outcomes following different impact trajectories. Acknowledgement: United States Department of Defense
[For poster presentation, poster board 33 on Thursday 5th September 2013]
88 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P25. Quintino Characterizing GDNF regulation and its impact in the of 6-OHDA rodent model Luis Quintino, Erika Elgstrand-Wettergren, Giuseppe Manfré, Christina Isaksson and Cecilia Lundberg CNS Gene Therapy, Wallenberg Neurocentrum, Sölvegatan 17, 22184 Lund, Sweden. (Email: [email protected]). Destabilizing domains (DD) regulate gene expression by targeting specific proteins fused to DD for destruction. More importantly, DD-regulated transgene expression can be stabilized using small molecules such as trimethoprim. Lentiviral vectors were used to deliver regulated glial cell-derived neurotrophic factor (GDNF-DD) to the striatum of rats. The expression of GDNF-DD was then turned ON using TMP in the drinking water. Three weeks after the expression was turned ON, the animals were lesioned with 6-OHDA. Initial studies showed that GDNF-DD was able to provide neuroprotection of substantia nigra neurons to levels comparable to wild-type GDNF. Histological analysis for GDNF activity using phoshorylated ribosomal protein S6 (pS6) showed a significant increase in the number of surviving pS6 positive nigral cells of 140% in the GDNF group and 77% in the GDNF-DD group where expression was turned ON. When the expression of GDNF-DD was turned OFF, only 30% of pS6 positive cells remained in the lesioned substantia nigra. This decrease was comparable to control groups. To determine if GDNF-DD expression could ameliorate or stop an ongoing degeneration or a fully lesioned brain, the expression of GDNF-DD was turned ON right after 6-OHDA lesion or 4 weeks after the animals were lesioned with 6-OHDA. Amphetamine-induced rotations were performed before lesion, 4 weeks after lesion and 9 weeks after lesion. In both groups where GDNF-DD expression was turned ON after immediately after lesion and 4 weeks after lesion there was a maintenance in the level of rotations. This was in contrast with control groups, where there was an increase of rotations through time, which reflected a progressive degeneration of SNpc. Histological analysis using pS6 also indicated a significant increase in the number of pS6 positive cells in both groups. The results indicate that the DD system is a promissing tool for regulating GDNF in vivo.
[For poster presentation, poster board 22 on Wednesday 4th September 2013]
89 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P26. Roberton Neonatal desensitisation to human embryonic tissue can be induced using a range of tissue types Victoria H. Roberton, Claire M. Kelly and Anne E. Rosser Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, Wales, UK. (Email: [email protected]). Prior to clinical application; safety and efficacy of potential human donor cells for transplantation in neurodegenerative disease must first be demonstrated in animal models. Neural xenografts are rejected by the rodent immune system within three weeks of implantation. Although immunosuppressant drugs are mostly effective short-term, toxic side-effects lead to termination of experiments before human cell differentiation. Immunodeficient hosts cannot withstand rigorous functional testing, rendering current methods inadequate for full preclinical assessment. We have developed a novel method in which host animals are “desensitised” to xenogeneic donor cells via an injection during the neonatal period, promoting acceptance of human neural xenografts in adulthood. Successful desensitisation has been demonstrated in rats using neonatal injections of human neural tissue. Desensitising with non-neural cells would release more valuable neural tissue for transplantation and would also inform on the immunological mechanisms underlying neonatal desensitisation. We compared survival of human transplants in the rat striatum in hosts desensitised neonatally with different human foetal tissues. Results suggest it may not be necessary for desensitising cell suspensions and transplanted cells to match, but that some tissue types may be more effective for desensitisation to xenogeneic tissue Acknowledgement: Work funded by the Wellcome Trust
[For poster presentation, poster board 39 on Thursday 5th September 2013]
90 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P27. Romanyuk Controlled release of neurotransmitters from biopolymer matrices influence neural stem cell proliferation and distribution Romanyuk N1, Vetrik M2, Karová K1, Jendelová P1,3, Hruby M2, Price J J.4 and Syková E 1,3 1Institute of Experimental Medicine and 2Institute of Macromolecular Chemistry, ASCR, Videnska 1083, 142 20 Prague-4; 3Department of Neuroscience, 2nd Faculty of Medicine, Charles University, Prague-5, Czech Republic; and 4Institute of Psychiatry, Kings College London, UK. (Email: [email protected]). Spinal cord injury (SCI) results in cavity formation and the loss of nervous tissue. Possible treatment can combine stem cells with matrix support and drug release in order to optimise the regeneration of lesioned tissue. We have utilized a heterogenic hydrogel system which releases cationic promoters that influence neural growth. The heterogenic ion exchanger Dowex 50WX8 was scattered in porous hydrogels based on 2-hydroxyethylmethacrylate or 2-hydroxypropylmethacryl- amide. Neurotransmitters and/or their analogs (carbachol, serotonin, L-dopamine and tryptamine) were bound to the ion exchanger. The release of carbachol and tryptamine increased cell proliferation by 20-30% compared to neural stem cells cultured in the presence of a control gel. Dopamine and serotonin significantly decreased cell proliferation. The growth and distribution of the cells in all hydrogels were analyzed immunohistochemically after 2, 7, 14, 21 and 28 days. We demonstrated that the cells were unable to attach and grow on the gel surface in the presence of dopamine, whereas tryptamine and carbachol supported both cell attachment and growth during 28 days. Our in vitro results demonstrate that the most suitable candidate for further in vivo experiments examining the combined treatment of SCI is a heterogenic hydrogel system releasing carbachol. Acknowledgments: P108/10/1560, 13-00939S.
[For poster presentation, poster board 38 on Thursday 5th September 2013]
91 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P28. Rumpel Transplantation of fetal ventral mesencephalic progenitor cells overexpressing high molecular weight FGF-2 isoforms in 6-OHDA lesioned rats Regina Rumpel 1, Alexander Klein 1, Andreas Ratzka 1, Meltem Özer 1,2, Maike Wesemann 1 and Claudia Grothe 1,2 1Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany; 2Centre for Systems Neuroscience (ZSN), Hannover Medical School, Hannover, Germany FGF-2 is one of the most potent neurotrophic factors to promote survival of dopaminergic (DA) neurons. It is expressed in different isoforms representing different translation products from a single mRNA. For this study we selected the high molecular weight (HMW) isoforms (21/23 kDa) since we could show that HMW FGF-2 transfected ventral mesencephalic (VM) cell preparations contained up to 3 times more DA neurons. After expansion and differentiation in vitro, HMW FGF-2 overexpressing embryonic day-12 VM cells were transplanted unilaterally into 6-OHDA lesioned rats. Goal of this ongoing study is to analyze the effects of HMW FGF-2 produced by the transfected VM cells as their “own” neurotrophic factor. The experimental design compares three grafted groups (HMW FGF-2 transfected, empty control vector transfected and non-transfected cells) with a lesioned control group. In addition, two different transplantation paradigms with a different amount of grafted cells are under evaluation. Animals are analyzed for behavioural performance for up to 12 weeks post transplantation and immunohistochemical measurements of DA neuron numbers and striatal re- innervation are studied. Characterizing these grafts will aim to advance understanding of the influence of transfected neurotrophic factors on survival and differentiation of DA cells.
[For poster presentation, poster board 9 on Wednesday 4th September 2013]
92 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P29. Seiler Antagonizing Nogo-receptor 1 promotes the number of cultured dopaminergic neurons and elongates their neurites Stefanie Seiler, Dario Pollini, Stefano Di Santo, Hans R. Widmer Department of Neurosurgery, Neurocenter and Regenerative Neuroscience Cluster, University of Bern, Switzerland. (Email: [email protected]). The myelin associated protein Nogo-A and its receptor NgR1 are among others the most potent growth inhibitors of the adult CNS. Nogo-A is mostly expressed on the surface of oligodendrocytes, but is also found in neurons of the adult and developing CNS. This suggests that Nogo-A serves additional functions in the brain. In the present study, we investigated the effects of antagonizing NgR1 on dopaminergic neurons. For that purpose ventral mesencephalic (VM) cultures from E14 rat embryos were grown in absence or presence of the NgR1 antagonist NEP1-40 for one week. Treatment with NEP1-40 significantly increased cell density of tyrosine hydroxylase (TH)-immunoreactive neurons. Morphological analysis of TH-positive neurons disclosed longer neurites and higher numbers of primary neurites in cultures incubated with NEP1-40, while soma size was not changed. Moreover, organotypic VM cultures displayed significantly bigger volume and higher TH-positive cell numbers after NEP1-40 treatment. Similarly, Western Blot analyzes showed increased expression levels of TH after NEP1-40 administration. In sum, our findings demonstrate that the intervention of Nogo-A signalling by antagonizing NgR1 modulates dopaminergic neuron properties in the developing midbrain. These observations might have substantial impact in the context of Parkinson’s disease. Supported by SNF and the Swiss Parkinson Foundation.
[For poster presentation, poster board 7 on Wednesday 4th September 2013]
93 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P30. Shin The anti-dyskinetic effect of dopamine receptor blockade is enhanced in parkinsonian rats following dopamine neuron transplantation Eunju Shin 1#, Carlo Lisci 2#, Elisabetta Tronci 2, Camino Fidalgo 2, Roberto Stancampiano 2, Anders Björklund 1 and Manolo Carta 2 1 Wallenberg Neuroscience Center, Lund University, Lund, Sweden; and 2 Department of Biomedical Sciences, Cagliari University, Monserrato, Italy. (# These authors have equally contributed to the study; E-mail: [email protected]).
We have previously shown that low doses of buspirone (5HT1A agonist and D2 receptor antagonist) and eticlopride (D2 receptor antagonist) can suppress graft-induced dyskinesia (GID) but are ineffective against L-DOPA-induced dyskinesia (LID) in a rat model of Parkinson’s disease. However, while the effect against GID was evaluated in grafted rats, the effect against LID was investigated only in non-grafted animals. Therefore, the present study was performed to investigate whether the graft might enhance the responsiveness of host striatum to these anti-dyskinetic drugs. If so, the same compounds should reduce LID only in grafted rats but not in non-grafted controls. Low doses of eticlopride (0.015 mg/kg), SCH23390 (0.1 mg/kg, D1 receptor antagonist), and buspirone (0.3 mg/kg) substantially reduced GID. As reported before, anti-GID effect of buspirone was not prevented by a selective 5-HT1A antagonist, suggesting that its effect is independent from 5-HT1A receptor agonism. Interestingly, the three compounds also potently reduced LID (induced by both 6 and 12 mg/kg L-DOPA) in grafted rats but were ineffective in non- grafted dyskinetic controls. Taken together, these data demonstrate that the dopamine cell grafts strikingly exacerbate the anti-dyskinetic effect of D1 and D2 antagonists against both GID and LID, and suggest that the anti-GID effect of buspirone in patients may be due to blockade of D2 receptors.
[For poster presentation, poster board 11 on Wednesday 4th September 2013]
94 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P31. Snyder 2 Proof-of-concept: The use of human induced pluripotent stem cells (hiPSCs) to uncover a novel developmentally-based target of therapeutic lithium in bipolar disease (BPD) B.T.D. Tobe 1,2§, A.M. Crain 1§, A.M. Winquist 1, M. Sidor 4, B. Calabrese 3, M. Brandel 1, C. Duerr 1, M. McCarthy 2, C. McClung 3, S. Halpain 3, I. Singec 1 and E.Y. Snyder 1 1Sanford-Burnham Medical Research Institute, 2 Dept. of Psychiatry, Veterans Admin. Med. Center, and 3Div. of Biol. Sciences, University of California San Diego, La Jolla CA, USA; and 4Dept of Psychiatry, University of Pittsburgh,, Pittsburgh PA, USA. (§equal contribution; Email: [email protected]). Neuropsychiatric disorders are difficult to model not only because their non-specific multigene pattern, but also because of the subjectivity by which they are often diagnosed. BPD, a highly-lethal illness, is unique in that 50% of patients respond to lithium. Indeed, lithium-responsiveness is often pathognomonic. Critically, lithium’s mechanism-of-action is unknown; however, were its targets to be identified, lithium could provide a molecular handle for discerning underlying mechanisms & deriving better treatments (lithium has unacceptable side-effects). We generated hiPSCs from lithium-responsive BPD patients from which neurons were generated. By performing differential proteomic analysis of “BPD neurons” exposed or not-exposed to lithium, we discovered a heretofore unanticipated lithium target, “CRMP2”, which plays a developmental role in neurite extension, cell migration, & channel activity by virtue of its association with tau & tubulin. We determined that GSK3β & IPP2A regulate CRMP2’s interaction with cytoskeleton; excessive CRMP2 phosphorylation causes neurite retraction. Li robustly reduces CRMP2 phosphorylation, validated in vivo in mouse hippocampus. Studies are ongoing supporting the prediction that CRMP2 mutation alters lithium responsiveness in mouse models of mania. Human material confirms an association between CRMP2 & BPD. We offer a strategy for merging hiPSC technology with proteomics to develop more effective neurotherapeutic drugs.
[For poster presentation, poster board 30 on Thursday 5th September 2013]
95 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P32. Strömberg Influx of blood monocytes to the brain is enhanced by antioxidants Rehnmark A, Lopes P, Faegermann E, Orädd G, Virel A, and Strömberg I Department of Integrative Medical Biology, Umeå University, Umeå, Sweden. (Email: [email protected]). Grafting in Parkinson's disease involves implantation of fetal tissue into the brain where an on-going robust neuroinflammation is present. The impact of the inflammation is still elusive, and therefore this study was focused on the neuroinflammatory process in the striatal 6-hydroxydopamine (6-OHDA) model of Parkinson's disease and the effects of antioxidant treatment. It is well known that the striatal neurotoxic injection causes neuroinflammation, however, the origin of the reactive microglia is not known, and suggestions have been made that some of the inflammatory cells are bone-marrow- derived. This has been studied utilizing radiation of the bone-marrow cells and implantation of tagged cells, however, this technique opens the blood-brain barrier. In this study, superparamagnetic iron oxide (SPIO) particles were combined with MRI. The SPIO particles were i.v. injected 24 h prior to the 6-OHDA lesion was performed. The rats were scanned for T2*-weighted images at 1 week post-lesion using a 9.4T Bruker BioSpec. T2*- weighted images are sensitive to iron, and the images become hypointense. The results revealed no significant difference between animals that received a striatal lesion with or without SPIO particles. Giving the animals antioxidants in the form of bilberry-enriched diet resulted in a significant striatal hypointensity compared to controls. The SPIO-particles were tagged with a fluerescent marker and immunohistochemical evaluations demonstrated that the particles were found in the lesioned striatum of antioxidant-fed rats. In animals given bilberry-enriched diet, striatal dopamine regeneration was found at later time points. Taken together, antioxidants promote influx of bone-marrow-derived monocytes to the injured area, and results in dopamine regeneration.
[For poster presentation, poster board 20 on Wednesday 4th September 2013]
96 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P33. Tajiri A microRNA profile of reduced mir-34b/c and increased mir-592 in adult epileptic patient-derived brain cells reveals potent disease biomarker and screening tool for transplantable stem cells Naoki Tajiri 1, 2, Hiroto Ishikawa 1, Kazutaka Shinozuka 1, Travis Dailey 1, Robert Sullivan 1, Yuji Kaneko 1, Teresita Malapira 1, Carmelina Gemma 1, Fernando Vale 1 and Cesar V. Borlongan1 1 Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, and 2 School of Physical Therapy & Rehabilitation Sciences, University of South Florida Morsani College of Medicine, Tampa, Florida, 33612, USA. (Email: [email protected]). This study reports the utility of microRNA profiling as a biomarker and therapy development for temporal lobe epilepsy (TLE). Expression profiling of microRNAs (miRNAs), confirmed by qRT-PCR, revealed that miR-34b and miR-34c were significantly up-regulated in the hippocampus and amygdala compared to the neocortex, with miR- 34b/c expression highest in the amygdala. In contrast, levels of miR-592 were significantly down-regulated in the hippocampus and amygdala compared to the neocortex. Immunocytochemical analyses provided insights into the functional role of these miRNAs, demonstrating decreased cell proliferation and differentiation in the hippocampus and amygdala compared to the neocortex of TLE patients. Stem cell grafts from the neocortex (i.e., reduced miR-34b/c but elevated miR-592 expression) survived in the amygdala, migrated to the lesioned hippocampus, and rescued hippocampal cell loss from the kainic acid-induced epilepsy in adult rats. ELISA revealed brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) were significantly down-regulated in the human hippocampus and amygdala compared to the neocortex, while basic fibroblast growth factor (bFGF) was significantly up-regulated in the hippocampus and amygdala compared to the neocortex. These results support the use of microRNA profiling as a biomarker and a screening tool for stem cell-based therapies targeting epilepsy.
[For poster presentation, poster board 32 on Thursday 5th September 2013]
97 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
P34. Tamburini Generation of cortical interneuron subtypes from human pluripotent stem cells Claudia Tamburini, Charles Arber, Meng Li Stem Cell Neurogenesis Group, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff CF10 3AX, UK. (E-mail: [email protected]). Cortical interneurons are heterogeneous local inhibitory neurons playing an essential role in maintaining a balanced activity in the cortex. Dysfunctions of these cells have been associated with several neurological and psychiatric disorders, such as schizophrenia, autism and epilepsy. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons offer great promise for modelling these diseases and serve as a platform for drug discovery. Furthermore, transplantation of stem cell-derived cortical interneurons may be developed as a therapy for epilepsy. However, comparing to some other clinically relevant neuronal cell types (e.g. dopamine neurons), our ability to direct cortical interneuron differentiation from human PSCs remains limited. We showed recently that Activin promotes neuronal differentiation by inhibiting the mitogenic Sonic Hedgehog pathway while enhancing the pro-neurogenic retinoic acid signalling. In addition, Activin promotes the acquisition of a Calretinin interneuron fate by providing a caudal ganglionic eminence identity in PSC-derived neural progenitors. Extending these findings, our current work employs different combinations of morphogens to induce MGE-like progenitors, which subsequently give rise to Parvalbumin and Somatostatin expressing interneuron subtypes. Acknowledgement. This work was funded by the UK Medical Research Council
[For poster presentation, poster board 34 on Thursday 5th September 2013]
98 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
P35. Teng Recovery neurobiology of spinal cord injury: mechanisms gleaned from peripheral neurotization studies Yang D. Teng 1,2, Denise Konya 1, Dou Yu 1, Jamie Anderson 1 and Xiang Zeng 1 1 Neurosurgery, Harvard Medical School and SCI Research, VABHS and 2 PM&R, Harvard Medical School and Spaulding Rehabilitation Hospital, Boston, USA (E-mail: [email protected]). We reported that neurotization, the surgical rerouting of intact peripheral nerves originating from spinal segments rostral to the site of injury to distal targets, could markedly improve motosensory function in rats with subacute hemisection (Konya’08) or contusion SCI (Yu’13). Unlike what had been assumed to trigger recovery (i.e., motor control rerouting) our data has engendered a novel hypothesis that central neuroplasticity including adapting afferent signals via the newly rerouted peripheral nerve and propriospinal projection network to invoke locomotion pattern generator may act for neural restoration. We propose to further discuss therapeutic effect of neurotization using data produced by rat models of hemisection and contusion SCI, including a 2-steps strategy of neural rerouting plus human mesenchymal stromal stem cell (hMSC) transplantation after chronic contusion SCI. Our work, as a bench-site progress, devises a clinically feasible procedure at both localized and systemic levels to treat traumatic SCI. Neurotization, as a peripheral approach of CNS repair, has long been studied, and even sporadically applied clinically. However, lack of understanding on the mechanisms has prevented its standardized applications. Since SCI remains an unmet medical demand, successful development of this treatment may greatly reduce suffering and cost for spinal cord trauma. (supported by CIMIT-DoD)
[For poster presentation, poster board 36 on Thursday 5th September 2013]
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P36. Thomas Caveolin-1 alters the amyloidogenic processing of amyloid precursor protein to amyloid- beta Rhian S. Thomas and Emma J. Kidd School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, U.K. (E-mail: [email protected]). Introduction: The ‘Amyloid Hypothesis’ suggests that the build-up of (Aβ) is a primary causal event in Alzheimer’s disease. Aβ is cleaved from amyloid precursor protein (APP) by the β- and γ-secretases, all of which have been identified in lipid raft-regions of the plasma membrane. Caveolae are specialised forms of lipid rafts, enriched with caveolin proteins. We examined whether expression of the most ubiquitous caveolin protein, caveolin-1, could affect the processing of APP into Aβ. Methods: Levels of caveolin-1 in astrocytoma cells were depleted by siRNA or over- expressed by delivering constructs carrying the myc-tagged caveolin-1 gene to these cells. Cells were lysed and media collected to detect intra- and extracellular protein levels of lipid raft proteins, APP and APP metabolites including Aβ. Results: After caveolin-1 levels were reduced by siRNA APP levels were unaffected, however, expression levels of Aβ were significantly increased Conversely, after over- expression of caveolin-1, APP levels were significantly reduced and expression levels of Aβ were unchanged. Conclusion: These results suggest that at normal physiological levels, caveolin-1 has a regulatory effect on Aβ and may provide a novel therapeutic target for this disease. Acknowledgement: This work was funded by BRACE.
[For poster presentation, poster board 35 on Thursday 5th September 2013]
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P37. Trigano Sedimentation of cell suspensions in large diameter cannulae: is it a problem? Trigano M 1, Torres EM 2 and Dunnett SB 2 1 Université Pierre et Marie Curie, Paris, FRANCE, and 2 Brain Repair Group, School of Biosciences, Cardiff University, Cardiff SF10 3AX UK. (Email: [email protected]). Cell transplantation using embryonic cells has been shown to be effective in animal models of Parkinson’s disease (PD) (Heuer et al., 2013, Torres et al., 2008) and Huntington’s disease, likewise in humans for treatment of PD (Mendez et al., 2002). A major difference between animal and human therapies is the size of the injection cannulae used. In rodent models cells are typically delivered using small cannulae with internal diameter of 0.159mm. In humans, larger cannulae with internal diameters of 0.5- 1.0mm will be needed and the question has arisen as to how cell suspensions will behave in such needles during the long surgical procedure. In this study, we investigate the behaviour of cell suspensions using injection cannulae of 2 different diameters. The data show that cell sedimentation occurs in both 0.5 and 0.8mm cannulae, in both vertical and horizontal orientations severely affecting the distribution of cells in the needle in a way that would produce a very uneven distribution of cells post injection. Acknowledgement. This work was funded by the EU FP7 TRANSEURO programme. References. Torres EM, Dowd E, Dunnett SB (2008). Neuroscience 154: 631-640 Heuer A, Vinh NN, Dunnett SB (2013). Eur J Neurosci 37: 1691-1704 Mendez I, Dagher A, Hong M et al. (2002). J Neurosurg 96: 589-596
[For poster presentation, poster board 3 on Wednesday 4th September 2013]
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P38. Vinh Comparison of mouse and human developing striatal gene expression Vinh NN, Kelly, CM, Heuer A, Precious SV, Allen ND, Kemp PJ and Rosser AE Brain Repair Group, School of Biosciences, Cardiff University, UK. (Email: [email protected]). Transplantation of neural cells derived from pluripotent stem cell sources in Huntington’s disease requires that they be directed towards a medium spiny striatal DAPRPP-32 positive neuronal phenotype. There are published reports of protocols to direct the differentiation of cells to an MSN phenotype that have shown success in terms of DARPP-32 readout, but limited functional effect of these cells is available to date. This would suggest that DAPRPP-32 alone is not sufficient to confirm a mature functional MSN neuron. Thus, there is a need to both understand more about the signals required for MSN development and to identify a profile of markers that are indicative of normal MSN differentiation. To this end, we have carried out a molecular and histological comparison of human and mouse whole ganglionic eminence (WGE) development across the period during which MSNs are generated. We performed QPCR of a range of known and potential striatal differentiation markers of WGE cells between E12 and E16 in the mouse and 6-12 weeks post conception in the human, and have attempted to correlate the striatal development between the two species. We also performed in situ hybridization and immunohistochemical analysis of sections over a similar developmental range for both species. We carried out electrophysiological analysis of human WGE cells over the same developmental period. For the first time, this provides key information on the genetic stages of human MSN development, and highlights some key species differences.
[For poster presentation, poster board 25 on Thursday 5th September 2013]
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P39. Wang Vascularization for neural repair and stem cell transplantation by hyaluronan- peptide hydrogels Ying Wang, Rongkai Ju, Shanshan Li,Yujun Wen, Shukui Yu and Qunyuan Xu School of Basic Medical Science, Beijing Institute of Brain Major Disorders, Capital Medical University, Beijing, China. (E-mail: [email protected]). Stem cell therapies are shown to be promising for diseases or injuries to the central nervous system (CNS), but the effect is limited so far. One of the reasons is microenvironment after CNS injury is not optimal for cell survival, especially due to the deficiency of angiogenesis in situ. Reconstruction of a blood vessel network for stem cells and injured tissue may play a key role for neural regeneration in the CNS. Here we have designed an angio-neurogenic hydrogel to promote angiogenesis and consequently to improve stem cell therapies for neural repair. The hydrogel was made by hyaluronan (HA), a main component of extracellular matrix, and linked with mimic peptides of vascular endothelial growth factor (VEGF) for providing a vascular microenvironment in injured area of the CNS. The scaffold did promote adhesion and proliferation of endothelia and neural stem cells effectively in vitro. Also, it evoked the receptors of VEGF and promoted the angiogenesis in vivo, when transplanted in injured brain. Our results suggest that functionalized hydrogels with peptides may provide a promising microenvironment for stem cells, and it should be a new approach for regenerative therapy of the injured nervous system.
[For poster presentation, poster board 37 on Wednesday 4th September 2013]
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P40. Yhnell The development of operant delayed matching to position for Huntington’s disease mouse models Emma Yhnell, Stephen B. Dunnett and Simon P. Brooks Brain Repair Group, School of Biosciences, Cardiff University, Museum Ave, Cardiff, UK. (Email: [email protected]). Operant delayed matching to position (DMTP) tasks are typically used in rats to probe spatial working memory and usually run in standard 2-lever operant “Skinner box” chambers. The DMTP task requires the animal to recall a previously made left or right response following various delay lengths, to obtain a reward. With the development of transgene technology there is a practical need to develop these tasks for mice. As part of a larger operant test battery we aimed to achieve this, utilising the operant 9-hole box mouse chamber, with nose-poke holes replacing levers. With no delays, C57BL/6J mice learned the DMTP operant task to >80% accuracy which decayed as a function of delay, demonstrating the viability of this task as a test of executive function for mice. The next phase of this work is to develop the reversal learning procedure, as both short-term memory and reversal learning are early disease signs in HD mice. Acknowledgement. This work was funded by the MRC.
[For poster presentation, poster board 23 on Thursday 5th September 2013]
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P41. Zhang AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in parkinsonian rat and mouse model Ting Zhang 1*, Xinmiao Ren 1, Xiaoli Gong 2, Guanzheng Hu 1, Wei Ding 3 and Xiaomin Wang 1,2 1 Department of Neurobiology, 2 Department of Physiology, 3 Department of Medical Genetics, Capital Medical University, Beijing, China. (E-mail: [email protected]). Parkinson’s disease (PD) is an aging-associated neurodegenerative disorder with progressive pathology involving the loss of midbrain dopaminergic neurons. Cerebral dopamine neurotrophic factor (CDNF) was recently discovered to be more selective and potent on preserving dopaminergic neurons than other known trophic factors. The present study examined the neuroprotective and functional restorative effects of CDNF overexpression in the striatum via recombinant adeno-associated virus type 2 (AAV2.CDNF) in MPTP lesioned mice and 6-hydroxydopamine (6-OHDA) injected rats. We found that bilateral striatal AAV2.CDNF injections, 2weeks before MPTP injections in C57/BL6 mice, improved Rotarod behavior. AAV2.CDNF pre-treatment increased tyrosine hydroxylase (TH)-immunoreactivity in the striatum. Striatal delivery of AAV2.CDNF 6 weeks after 6-OHDA injections in SD rats, was able to recover behavior deficits and resulted in a significant restoration of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and TH-ir fiber density in the striatum. Meanwhile, long-term administration of AAV2.CDNF didn’t interfere TH expression in rat striatum. Our results indicate that striatal administration of AAV2.CDNF was able to provide effective neuro-protection and neuro-restoration in the nigrostriatal system and that it may be considered for future clinical applications in PD therapy. This work was funded by National Natural Science Foundation of China (31000476).
[For poster presentation, poster board 14 on Thursday 5th September 2013]
105 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
LOGO PRIZE
The Local and International Organising Committee are pleased to congratulate
Luis Azmitia Henriquez
For his submission of the winning design in the competition to design a logo for the INTR12 International Symposium.
The winning design has been used on the cover of the conference booklet, on the web page and on other promotional material.
The winner is awarded free registration to the meeting, and has been guaranteed a travel grant to attend and a bottle of champagne to celebrate.
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TRAVEL AWARD WINNERS
The Local and International Organising Committee are pleased to congratulate the following winners of travel awards to attend the INTR12 International Symposium.
Luis Azmitia Henriquez (Germany) Virginia Mattis (USA) Amy Evans (UK) Meltem Özer (Germany) Marija Fjodorova (UK) Federica Rinaldi (UK) Genevieve Gowing (USA) Regina Rumpel (Germany) Síle Griffin (UK) Daniella Rylander (Sweden) Andreas Heuer (Sweden) Stefanie Seiler (Switzerland) Nadin Hoffmann (Germany) Gaynor Ann Smith (USA) Pia Jensen (Denmark) Naoki Tajiri (USA) Zania Kefalopoulou (UK) Ying Wang (China) Mariah Lelos (UK) Jordan Wright (Australia)
All applications were rated by the International Organising Committee and ranked accordingly. The winners will be presented with award cheques at the business meeting on the afternoon of Thursday, 5th September. With a large number of applications received, the competition was highly comp- etitive; we regret that other applicants will inevitably be disappointed, but we congratulate all of them in still finding a way to make it to the meeting.
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CONFERENCE PROCEEDINGS
The Abstracts, Short Reviews and selected Research Reports presented at INTR12 will be published in a separate issue of the rapid publication journal NeuroReport, to appear on line approx. 8 weeks from the close of the symposium. All Abstracts accepted for presentation at the meeting will be included in the published proceedings as well as in the conference hand-out. Short reviews and research reports are by invitation, for submission prior to the symposium. Keynote speakers have been invited to prepare short focussed commentaries or reviews relating to the topic of their presentation. These are not intended to be comprehensive reviews of a field but focussed commentaries on specific topics of current interest and debate at the cutting edge in the field. A selection of submitted abstracts have also been invited for submission as short research reports, following the appraisal and suggestions from the Local and International Pro- gramme Committees. All manuscripts will be peer reviewed. To ensure timely publication, invited manuscripts should be submitted to the Editor-in Chief (Dr. Rosemary Fricker, [email protected]) by Friday 30th August 2013. The editor will organise rapid review during the meeting with the goal to provide feedback, discussion and hopefully a ‘revise’ or ‘accept’ decision by the end of the meeting, and a time line for return of finalised versions can then be negotiated with the authors directly. If invited to submit a proceedings review, guidelines for the preparation of manuscripts are found on the NeuroReport website at http://edmgr.ovid.com/nr/accounts/ifauth.htm. Please read and review the guidelines carefully. Articles that are not submitted in accordance with the instructions and guidelines are more likely to require revision. Recommendations for other manuscripts for inclusion in the proceedings should be made in discussion with the Editor-in-Chief. For further advice contact the Editor-in-Chief, Dr. Rosemary A. Fricker. Email: [email protected].
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SATELLITE EVENT
TRANSEURO WORKSHOP: Taking cell therapies from lab bench to clinic Monday September 2nd – Tuesday September 3rd Cardiff University School of Biosciences and the Welsh School of Pharmacy. Summary description of workshop: Cell-based therapies are being widely developed to treat a variety of degenerative disorders but there are numerous hurdles to be overcome. Initial studies are using foetal tissue or neuronal precursor cell lines but the future will be based on the use of other stem cell sources. In addition to the logistical problems of choosing the cell source, mass production of cell lines, management of clinical trials, techniques and procedures also have to comply with European Union legislation on Good Manufacturing Process (GMP). This brings with it a host of further considerations and this workshop intends to highlight the processes that need to be undertaken and considered. In a series of talks we will be addressing the issues described above with the addition of a unique opportunity to experience working in a GMP facility within Cardiff University School of Pharmacy and Pharmaceutical Sciences. Speakers Claire Foster-Gilbert Ethical considerations in cell transplantation Emma Lane Preclinical models of transplantation Mike Modo In vivo imaging modalities for tracking transplanted cells Paul Whiting Clinical trials in the eye (regulatory hurdles) Charlie Hunt Regulation, licensing and processing clinical grade cells Peter Andrews Characterisation of stem cell lines Stephen Minger Stem cells for drug discovery (an industrial perspective) Roger Barker Managing clinical trials in cell transplantation Eduardo Torres GMP : nuts and bolts Catherine Talbot GMP in practice
For further information: Eduardo Torres; email [email protected]; tel 02920 874115.
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CONFERENCE HOTELS
Hilton Hotel Cardiff (the conference hotel) Address: Kingsway, Cardiff CF10 3HH Website: www.hilton.com/cardiff Contact tel: +44 (0)2920 646 300
Park Plaza (100 metres from the conference centre) Address: Greyfriars Road, Cardiff, CF10 3AL Website: www.parkplazacardiff.com Contact tel: +44 (0)2920 111 111
Parc Thistle (200 metres from the conference centre) Address: Parc Place, Cardiff CF10 3UD Website: www.thistle.com/The-Parc Contact tel: +44 (0)845 305 8311
Angel Hotel (300 metres from the conference centre) Address: Castle Street Cardiff, CF10 1SZ Website: www.pumahotels.co.uk/hotels/ Contact tel: +44 (0)2920 649 200
Holiday Inn (300 metres from the conference centre) Address: Castle Street, Cardiff CF10 1XD Website: www.holidayinn.com/cardiff Contact tel: +44 (0)871 423 4876
University Student Accommodation (400 metres from the conference centre) Address: Senghenydd Hall, Senghenydd Road CF24 4A Website: http://www.cardiff.ac.uk/for/prospective/accom modation/residences/senghennydd-hall.html Contact tel: +44 (0)871 423 4876
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HOTEL MAP
111 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
LOCAL AMENITIES, SHOPPING AND DINING Local Travel Central Cardiff is compact and most destinations in the city centre are easily accessible on foot. Central Cardiff is well served by busses for a little further afield into the outskirts. Also the Valley line trains are regular and serve many local destinations within a 20 mile radius. Cardiff Bay is just a bit too far to walk and passes through some rather unsavoury areas, so three options: (i) take a taxi, (ii) local trains from Cardiff Queen Street station, run approx. every 12 mins until 11:54pm. or (iii) a water taxi operates from the river stop at the southwest corner of Cardiff Castle to Cardiff Bay, running approx. every 30 mins on the half hour, all day until sunset. Local Shopping The main shopping streets are Queen Street, the Hayes, and St Mary’s Street. These main streets are intersected by a network of covered arcades, for which Cardiff is famous, comprising mostly specialist and boutique shopping. There are several department stores of various styles and quality. Many consider that the John Lewis store at the bottom end of the Hayes is good reliable quality and meets all needs. For any and all queries please ask at the Conference Desk, or indeed any of the locally-based participants at the meeting, for a myriad of diverse suggestions! Pharmacy Comprehensive pharmacy facilities are available at the local Boots the Chemist, located 200 yards from the Hilton on 36 Queen Street CF10 3RG (the pedestrian precinct running eastwards from the south eastern corner of the castle, the Hilton being at the north east corner). Opening hours 8am to 8pm M-F daily. Banks Branches of all main UK banks are available on Queen Street, St Mary’s Street or the Hayes, radiating from the south east corner of the castle. If in doubt, please enquire at the Conference Desk.
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Local Restaurants and Bars In the city centre: Fast foods and burgers to meet any taste are ubiquitous, but think about trying: Browns Restaurant (The Friary, 30 yards from the Hilton; 02920 066 7096). Classic brasserie style, good reliable quality from a relatively unimaginative menu. Jamie’s Italian (St David’s Shopping Centre; 02920 002 7792). Jamie Oliver’s gastro bistro, good value, imaginative menus, and actually quite good for all that. The Potted Pig (27 High Street, below Zizzi; 02920 22 48 17). A carnivore’s delight, pork in all its variations and many other roast meats and traditional dishes. Las Iguanas (8 Mill Lane, bottom end of the Hayes; 02920 226 373). Classic Mexican, tapas and fajitas, chimichangas and enchiladas for mains. Le Monde (60 St Mary Street; 02920 2038 7376). Fine seafood and steak restaurant – the days dishes on the chalkboard, select your fish from the slab. Zizzi (27 High Street; 02920 645110). Popular, good value Italian chain, pizza, pasta and risotto. In the Bay If the weather is nice, there is nothing more pleasant than an evening to wander round the bay area and dining al fresco (but no promises, it is September in Wales!). The dining tends to be more varied and exotic than in the city centre. Woods Brasserie (the Pilotage Building, Stuart Street; 02920 492 400). Traditional high quality brasserie with excellent food and wines, on the waterside. Wagamama (Mermaid Quay, upper level; 02920 49 9407). Cult Japanese noodle restaurant, with wide range of ramen, rice and pan-fried noodle dishes. Pearl of the Orient (Mermaid Quay, upper level; 02920 498080). Chinese fine dining. Excellent crispy Peking duck with the set meals, all you can eat lunches. Entrecôte (Mermaid Quay, upper level; 02920 490 990). Has replaced the much loved Garçon Toulouse-style French bistro with a more upmarket Parisian-style café restaurant. French classic dishes, with fine wine and a proper cheese chariot. And lots, lots more in close proximity. Wander, browse and follow your nose.
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TRAVEL TO AND FROM CARDIFF By Road … An interactive map for driving directions to Cardiff and locating the Hilton hotel is to be found on the Hilton website (www3.hilton.com/en/hotels/united-kingdom/ hilton-cardiff-CWLHITW/maps-directions/index.html).
By Train … (National Rail timetables, prices and ticket purchase : www.nationalrail.co.uk) The Hilton hotel is 10 minutes’ walk, (5 min ride by taxi) from Cardiff Central mainline station. Fast and comfortable (but expensive) rail service provided by First Great Western from London Paddington. There are good savings to be made by booking your ticket in advance for a particular train, and travelling outside the rush hour period (£210 open return ticket, but as low as £27 each way off-peak non-changeable advance bookings). More picturesque cross country services that are slower but less expensive from Manchester, Birmingham etc. Beware! when on the train, station signs are in Welsh as well as English: Cardiff (Caerdydd) is next stop after Newport (Cas Newydd).
By Air … Cardiff International Airport (http://www.tbicardiffairport.com) has good national connections to other UK regional airports (Edinburgh, Glasgow, Belfast) and scheduled international connections from Dublin, Paris (CDG) and Amsterdam. KLM operates several flights per day to and from Schiphol so that Amsterdam offers the most convenient European hub. Alternatively Ryanair, serves several airports from Ireland, and FlyBe links to other UK destinations. Cardiff airport is a 30 minute taxi ride from the centre of Cardiff (price ~ £30). Bristol International Airport (www.bristolairport.co.uk) has better international connections than Cardiff but is an hour away by road (taxi ~£100) or 2 hours by airport bus service to Bristol Temple Meads station, train Bristol to Cardiff Central, and a local taxi ride to the hotel (approx. £23 in total). London Heathrow is the major international airport serving London and the south of the UK, with good international connections. From Heathrow, take the Heathrow Express train into Paddington Station in central London, and change to the First Great Western Intercity train, 2 hours to Cardiff Central .
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YOUR MORNING EXERCISE - WALK, JOG OR CYCLE
The entrance to Bute Park is located at 100 metres diagonally opposite the entrance to the Hilton Hotel. The Park offers trails, woodlands and playing fields, flourishing in wild-life, but all in the centre of the city.
Recent sightings include goosander, kingfisher, dipper, otter and mink, although the ubiquitous lesser black back gulls are easier to spot (and hear).
The track alongside the river to Blackweir [1] is about a mile each way, or cross the river at Blackweir to return through the playing fields on the west side of the river, and cross back into the park by the Sophia Gardens footbridge [13].
From Blackweir, the Taff trail continues on the towpath alongside the river northwards (with a good surface for walking and cycling). You will pass under the Gabalfa inter- change and reach further weirs at Whitchurch. Beyond that the trail winds ever onwards and upwards, out of the city, past Castell Coch, up through the mining valleys and eventually across the Brecon Beacons to the picturesque ancient town of Brecon itself.
↘ Entrance to Hilton, 50 yards diagonally opposite
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THINGS TO DO IN CARDIFF, SEPTEMBER 2013 … For when you have gaps in your busy meeting schedule, or things to do before or after the symposium: Cardiff City Cardiff {http://whycardiff.com/live-in-cardiff.html} is the capital city of the small but very proud nation of Wales. Known for being the seat of Welsh government and the National Assembly (in Cardiff Bay), home of Welsh rugby (the Millennium stadium), and a vibrant cultural city of parks, music and a vibrant night life. The Centenary Walk guide provides a short walking tour of the key sites close to the hotel. For science fiction fans, Dr. Who {http://www.visitcardiff.com/the-home-of-doctor-who} and Torchwood are produced and largely filmed in Cardiff, as also is the TV series Sherlock. For the shopaholics, the centre of the city is criss-crossed with six historic arcades {http://www.visitcardiff.com/shopping/historic-arcades} of small cafés, delis and boutique stores, located within 200 yards from the conference venue. Cardiff Castle In the heart of the capital city is Cardiff Castle, a truly remarkable site with a history that spans over 2000 years. ‘Eccentric genius’ architect William Burges was given free rein to create the amazingly lavish and opulent interiors; each breath-taking room rich with murals, stained glass, gilding and superb craftsmanship.
The National Museum of Wales The National Museum brings together art, archaeology, natural history and geology. Follow Wales's amazing journey from the very beginning of time to the present day. Everyday objects and beautiful artefacts tell the stories of the people of Wales and explore our links with the past. The INTR12 opening reception and plenary lecture on Tuesday 3rd September, will be held in the National Museum galleries. Located 100 yards from the main conference hotel, you can pop back to browse specific collections at any time you have a break in your programme – admission is free, just walk in. Bute Park and the Animals’ Wall The Animal Wall, alongside Cardiff Castle, is one of the most delightful and photographed historic features in Cardiff. It was designed by architect William Burges for the 3rd Marquis of Bute.
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Cardiff Bay In Cardiff Bay, the Wales Millennium Centre stands next to the Grade 1 listed Pierhead building. The Norwegian Church, where children's author Roald Dahl was christened, is now an arts centre and cafe with a Nordic flavour. The futuristic National Assembly building is the seat of Welsh government.
The Millennium Centre Wales Millennium Centre opened in 2004 and has already established its reputation as one of the world`s iconic arts and cultural destinations. The vision of the Centre is to be an internationally significant cultural landmark and centre for the performing arts, renowned for inspiration, excellence and leadership. The Centre is one of the most lively performing arts centres in Europe. Look beyond the amazing exterior, as featured in Torchwood and Dr. Who, and you will come across a bustling atmosphere that makes our visitors want to return time and time again. The Millennium Centre is home to Welsh National Opera, one of the world’s premier opera companies.
The Millennium Stadium The home of Welsh rugby right in the heart of the city. Breath in the atmosphere, sense the passion – “Cymru am byth”
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And a little further afield … Castell Coch (the ‘Red Castle’) (4 miles to the north of Cardiff) A 19th-century Gothic Revival castle built on the remains of a genuine 13th-century fortification re-designed by William Burgess, it is situated on a steep hillside high above the village of Tongwynlais. It is clearly visible on the horizon from the centre of town.
Museum of Welsh Life (St Fagans, 5 miles, towards the west) Just outside Cardiff, St Fagans National History Museum is one of the world's best open-air museums. Set in the grounds of St Fagans Castle the museum is home to over 40 original historical buildings. As a living museum you'll find craftsmen demonstrating their skills. The Brecon Beacons National Park (45 miles, towards the north) With Pen-y-fan the highest peak standing at 886m, the Brecon Beacons mountain range offers wilderness on your doorstep, for enjoyable walks, stunning vistas, challenging climbing, always under the gaze of the local sheep, kite, and wild mountain ponies
Pwll Mawr (the ‘Big Pit’ coal mining museum, 24 miles to the north west) The National Coal Museum is a real coal mine and one of Britain's leading mining museums. With facilities to educate and entertain, Big Pit is an exciting and informative day out. For more industrial history, Rhondda Heritage Park offers a fascinating insight into the rich culture and character of the Rhondda mining valleys. “How Green was my Valley” – visit the set.
Caerleon Roman Fort and Baths (18 miles to the north east). The National Roman Legion Museum at Caerleon displays a remarkable collection of finds from Roman Caerleon, the base of the second Augustan Legion, the furthest outpost of the Roman Empire.
118 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
MEETING PARTICIPANTS
Robin Ali Roger Barker email: [email protected] email: [email protected] tel: +44 207 608 4023 tel: +44 1223 331169 Institute of Ophthalmology, University College Centre for Brain Repair, Addenbrooke’s London, 11-13 Bath Street, London EC1V 9EL, Hospital, Cambridge CB2 0PY, UK UK. Anders Björklund Arturo Alvarez-Buylla email: [email protected] email: [email protected] tel: +46 46 222 0540 tel: +1 415 514 2348 BMC, A11 Sölvegatan 17, 22184 Lund, Sweden Dept of Neurological Surgery, UCSF, Box 0525, Central Campus, HSIR West 1201F, San Cesar Borlongan Francisco, CA 94143-0525, USA email: [email protected] tel: +1 813 974 3988 Peter Andrews Department of Neurosurgery, University of email: [email protected] South Florida College of Medicine, 12901 Bruce tel: +44 114 222 4173 B Downs Blvd, Tampa, Florida 33612, USA Dept of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TH, UK Kieran Breen email: [email protected] Romina Aron Badin tel: +44 20 7963 9325 email: [email protected] Parkinson's UK 215 Vauxhall Bridge Road tel: +33 1 46 54 85 29 London SW1V 1EJ, UK MIRCen CEA, CNRS 2210, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France Ludivine Breger email: [email protected] Luis Azmitia tel: +44 7967 146399 email: [email protected] Flat 6, Hardwick House, King Street, Norwich tel: +49 0176 7072 9617 NR1 1DB, UK Breisacherstraße 64, PLZ 79106, Freiburg i.Br., Germany Simon Brooks email: [email protected] Peter Barbuti tel: +44 02920874115 email: [email protected] Brain Repair Group, School of Biosciences, tel: +44 7859 007436 Cardiff University, Museum Avenue, Cardiff University of Bristol, Dorothy Hodgkin Building, CF10 3AX, UK Whitson Street, Bristol BS1 3NY, UK Andrew Bubak Yves-Alain Barde email: [email protected] email: [email protected] tel: 1-605-481-0349 School of Biosciences, Cardiff University, 2100 N. Ursula St., Unit 1-304, Aurora CO Museum Avenue, Cardiff CF10 3AX, UK 80045, USA
119 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
Maeve Caldwell Stefano Di Santo email: [email protected] email: [email protected] tel: +44 117 3313043 tel: +41 31 632 2773 Henry Wellcome LINE, Dorothy Hodgkin University Clinic for Neurosurgery, Building, Whitson Street, Bristol, BS1 3NY, UK Neurosurgery Research Lab, Pavillon 47, Inselspital, 3010 Bern, Switzerland Siddharthan Chandran email: [email protected] Claris Diaz tel: +44 131 465 9519 email: [email protected] MRC Centre for Regenerative Medicine, tel: +44 2920 875762 University of Edinburgh, Queens' Medical Brain Repair Group, Cardiff School of Research Institute, Edinburgh EH16 4TJ, UK Biosciences, Museum Avenue, Cardiff CF10 3AX, Wales UK Narawadee Choompoo email: [email protected] Eilis Dowd tel: +44 2920 874684 email: [email protected] Brain Repair Group, School of Biosciences, tel: + 353 91 492 776 Cardiff University, Museum Avenue, Cardiff Pharmacology & Therapeutics, National CF10 3AX, UK University of Ireland Galway, Galway, Ireland
Pete Coffey Wei-Ming Duan UCL Institute of Ophthalmology email: [email protected] [email protected] tel: +86 10 8395 0068 tel: +44 207 608 4039 Department of Anatomy Capital Medical Division of Cellular Therapy, Institute of University No. 10 Xitoutiao, Youanmenwai Ophthalmology, 11-43 Bath Street, London Fengtai District, Beijing 100069, China EC1V 9EL, UK Stephen Dunnett Ruth Concannon email: [email protected] email: [email protected] tel: +44 2920 875188 tel: +353 87 760 3326 Brain Repair Group, School of Biosciences, Clonboo, Corrandulla, Co. Galway, Ireland Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK Jeff Davies email: [email protected] Kelly Erikson tel: +44 1792 602209 email: [email protected] Institute of Life Sciences, College of Medicine, tel: +44 7528 505997 Swansea University, Swansea SA2 8PP, UK 35 Lock Keepers Court, Blackweir Terrace, Cardiff CF10 3EZ, UK Vanessa Davies email: [email protected] Amy Evans tel: +44 2920 688340 email: [email protected] Neuroscience and Mental Health Research tel: +44 7070 718617 Institute, Cardiff University, Maindy Road, Brain Repair Group, School of Biosciences, Cardiff CF24 4HQ, UK Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK
120 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
Sir Martin Evans Steven Gill email: [email protected] email: [email protected] Chancellor, Cardiff University, Park Place, Neurosciences, Frenchay Hospital / North Cardiff CF10 3AT, UK Bristol Trust, Bristol BS16 1LE, UK
James Fawcett Genevieve Gowing email: [email protected] email: Genevieve Gowing tel: +44 1223 331160 tel: +1 310 248 8571 The Brain Repair Centre, University of Cedars-Sinai Medical Center, Regenerative Cambridge, Forvie Site, Robinson Way, Medicine Institute, 8405AHSP, 8700 Beverly Cambridge CB1 6JY, UK Boulevard, Los Angeles CA 90048, USA
Maria Fjodorova Liam Gray email: [email protected] email: [email protected] tel: +44 2920 875762 tel: +44 2920 744367 Brain Repair Group, School of Biosciences, Dept of Neurosurgery, Cardiff University Cardiff University, Museum Avenue, Cardiff School of Medicine, UHW Main Building, Heath CF10 3AX, UK Park, Cardiff CF14 4XN, UK
Clare Foster-Gilbert Síle Griffin email: Claire.Foster-Gilbert@westminster- email: [email protected] abbey.org tel: +44 1782 33058 tel: +44 207 654 4809 School of Life Sciences Huxley Building, Keele Westminster Abbey Institute, The Chapter University, Newcastle-under-Lyme, ST5 5BG, Office, 20 Dean's Yard, London SW1P 3PA, UK UK
Rosemary Fricker William Griffiths email: [email protected] email: [email protected] tel: +44 1782 733874 tel: +44 1792 295562 Schools of Medicine, Life Sciences and ISTM, College of Medicine, Swansea University, Huxley Building, Keele University, Keele, Staffs Singleton Park, Swansea SA2 8PP, UK ST5 5BG, UK John Gurdon Charlie Geater email: [email protected] email: [email protected] tel: +44 1223 334090 tel: +44 2920 879069 Welcome Trust/CRUK Gurdon Institute, Tennis Cardiff School of Biosciences, The Sir Martin Court Road, Cambridge CB2 1QN, UK Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK Annelie Handreck email: [email protected] Manuela Gernert tel: +49 511 953 8594 email: [email protected] Department of Pharmacology, Toxicology, and tel: +49 511 9538527 Pharmacy, University of Veterinary Medicine Dept. of Pharmacology, Toxicology, and Bünteweg 17, 30559 Hannover, Germany Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany
121 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
Philippe Hantraye Charlie Hunt email: [email protected] email: [email protected] tel: +33 1 46 54 83 67 tel: +44 1707 641559 MIRCen CEA CNRS 2210, 18 Route du UK Stem Cell Bank, National Institute for Panorama, 92265 Fontenay-aux-Roses, France Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, David (Harri) Harrison Hertfordshire, EN6 3QG, UK email: [email protected] tel: +44 2920 874684 Pia Jensen Brain Repair Group, School of Biosciences, email: [email protected] Museum Avenue, Cardiff CF10 3AX, UK tel: +45 61 66 0874 Pia Jensen J.B. Winsløws Vej 21 st, 5000 Andreas Heuer Odense C, Denmark email: [email protected] tel: +46 46 222 3418 Christine Kaindlstorfer BMC A11, Sölvegatan 17, 22184 Lund, Sweden email: [email protected] tel: +43 512 5042 7432 Deirdre Hoban Medical University Innsbruck, Anichstraße 35, email: [email protected] 6020 Innsbruck, Austria tel: +353 85 7293254 Department of Pharmacology and Jessica Kauhausen Therapeutics, CNS Lab, Distillery Road, NUIG, email: [email protected] Galway tel: 60435794717 43-45 Sanctuary Close, Werribee, 3030 Nadin Hoffmann Victoria, Australia email: [email protected] tel: +49 761 270 50460 Zinovia Kefalopoulou Neurozentrum AG Stereotaxy and email: [email protected] Interventional Neuroscience, Breisacher Straße tel: +44 7553246776 64, 79106 Freiburg, Germany 33 Queen Square, Unit of Functional Neurosurgery, 2nd Floor, Box 146, London Cath Hortop WC1N 3BG, UK email: [email protected] tel: +44 2920 688341 Emma Kidd Neuroscience and Mental Health Research email: [email protected] Institute, Cardiff University, Maindy Road, tel: +44 2920 875803 Cardiff CF24 4HQ, UK School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, Hongyung Huang King Edward VII Avenue, Cardiff, CF10 3NB, UK email: [email protected] tel: +86 139 1011 6608 Jeff Kordower Department of Neurosurgery, Beijing email: [email protected] Rehabilitation Hospital, Capital Medical tel: +1 312 563 3570 University, Beijing, China Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA
122 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
Emma Lane, NECTAR President Stephen Minger email: [email protected] email: [email protected] tel: +44 2920 874989 tel: +44 2920 526441 Cardiff School of Pharmacy and Pharmaceutical GE Healthcare, Maynard Centre, Forest Farm, Sciences, Cardiff University, Redwood Building, Whitchurch, Cardiff CF14 7YT, UK King Edward VII Avenue, Cardiff, CF10 3NB, UK Hideki Mochizuki Katie Le Blond email: [email protected] tel: +44 20 7963 9325 tel: +81 6 6879 5111 Parkinson's UK, 215 Vauxhall Bridge Road Department of Neurology, Osaka University London SW1V 1EJ , UK Graduate School of Medicine 2-2 Yamadaoka, Suita Osaka, 565-0871 Japan Mariah Lelos email: [email protected] Mike Modo tel: +44 2920 874112 email: [email protected] Brain Repair Group, School of Biosciences, tel: +1 412 383 7200 Cardiff University, Museum Avenue, Cardiff McGowan Institute, University of Pittsburgh, CF10 3AX, UK 3025 East Carson Street, Pittsburgh PA 15203, USA Meng Li email: [email protected] Christelle Monville tel: +1 813 974 1377 email: [email protected] Neuroscience and Mental Health Research tel: +33 1 69 90 85 28 Institute, Cardiff University, Maindy Road, 5 rue Henri Desbruères, 91030 Évry, France Cardiff CF24 4HQ, UK Sarah Moore Alberto Martínez-Serrano email: [email protected] email: [email protected] tel: +44 7847 206176 tel: +34 91 196 4620 John Van Geest Centre for Brain Repair, E.D. Center of Molecular Biology 'Severo Ochoa', Adrian Building, Forvie Site, Robinson Way, Laboratory 305 C, Nicolas Cabrera 1, UAM- Cambridge CB2 0PY, UK Campus, Cantoblanco, 28049-Madrid, Spain Alun Morgan Virginia Mattis email: [email protected] email: [email protected] tel: +44 1656 663284 tel: +1 310 248 8560 Bridgend Parkinson’s UK 8700 Beverly Blvd, AHSP 8405, Los Angeles CA 90048, USA Radha Nair-Roberts email: [email protected] Su Metcalfe tel: +44 2920 874115 email: [email protected] Brain Repair Group, School of Biosciences, tel: +44 1223 570716 Cardiff University, Museum Avenue, Cardiff John van Geest Centre for Brain Repair, CF10 3AX, UK Addenbrooke’s Hospital, Cambridge CB2 0PY, UK
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Carol Naughton Claire Parish email: [email protected] email: [email protected] tel: +353 87 904 3321 tel: +61 3 9035 6526 Logatemple, Claremorris, Co. Mayo, Ireland Florey Neuroscience Institute, The University of Melbourne, Parkville, Victoria 3010, Ben Newland Australia email: [email protected] tel: +353 85 129 7954 Malin Parmar Nant-y-Ferwig, Gwbert Road, Cardigan, email: [email protected] Ceredigion SA43 1PN, Wales UK tel: +46 46 222 06 20 Developmental Neurobiology Unit, Wallenberg Rowan Orme Neuroscience Center, Lund University, 221 84 email: [email protected] Lund, Sweden tel: +44 7877 326011 Cardiff University School of Medicine Henry Marta P Pereira Wellcome Building 4th Floor Heath Park Cardiff email: [email protected] CF10 4XN tel: +34 91 196 4650 Centro de Biologia Molecular Severo Ochoa, Mike Owen Nicolas Cabrera 1, lab.305 Cantoblanco [email protected] (Campus UAM), 28049-Madrid, Spain tel: +44 2920 687065 Neuroscience and Mental Health Research Luis Quintino Institute, Cardiff University, Maindy Road, email: [email protected] Cardiff CF24 4HQ, UK tel: +46 7384 43256 CNS Gene Therapy, Wallenberg Neurocentrum Meltem Özer (BMC A11), Sölvegatan 17, 22184 Lund, email: [email protected] Sweden tel: +49 1777 998576 Heinrich-Stamme-Str.1, 30171 Hannover, Sandip Raha Germany email: [email protected] tel: +44 1656 752060 Mibel M. Pabón Movement Disorders Clinic, Princess of Wales email: [email protected] Hospital, Coity Road, Bridgend CF31 1RQ, tel: +1 813 974 3510 South Wales, UK University of South Florida 12901 Bruce B. Downs Blvd, MDC-78, Tampa Florida 33612, James Rakshi USA Email: [email protected] tel: +44 7732 955546 Stéphane Palfi 14 Westbere Road, London NW2 3SR, UK email: [email protected] tel: +33 1 49 81 22 03 Conor Ramsden Henri Mondor Hospital – Neurochirurgie, email:[email protected] 51 avenue du Marechal de Lattre de Tassigny, tel: +44 207 608 4061 94000 Créteil, France The London Project to Cure Blindness, Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
124 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
Sarah-Jane Richards Stefanie Seiler email: [email protected] email: [email protected] tel: +44 7584 374153 tel: +41 632 27 73 Secure Law, 2a Oaktree Court, Mulberry Drive, Inselspital Universitätsklinik für Cardiff Gate, Cardiff 23 8RS, UK Neurochirurgie, Neurochirurgisches Forschungslabor Pavillon, 41 Freiburgstrasse Federica Rinaldi 3010 Bern, Switzerland email: [email protected] tel: +44 7582 375161 Brandon Shelley Bristol University, Dorothy Hodgkin Building, 1, email: [email protected] Whitson street BS3 1NY Bristol, UK tel: +1 310 248 8573 Cedars-Sinai Medical Center, 8700 Beverly Victoria Roberton Blvd., AHSP 8405, Los Angeles CA 90048 USA email: [email protected] tel: +44 7772 509861 Eunju Shin Brain Repair Group, School of Biosciences, email: [email protected] Cardiff University, Museum Avenue, Cardiff tel: +46 46 222 0555 CF10 3AX, UK Lund University BMC A11, Sölvegatan 17, 22184 Lund Sweden Nataliya Romanyuk email: [email protected] John Sladek tel: +42 24 106 2827 email: [email protected] Videnska 1083, 142 20, Prague-4, Czech tel: +1 303 724 0629 Republic Department of Neurology, University of Colorado School of Medicine, 12800 E. 19th Anne Rosser Ave., Aurora CO 80045, USA email: [email protected] tel: +44 2920 876654 Gaynor Smith Brain Repair Group, School of Biosciences, email: [email protected] Cardiff University, Museum Avenue, Cardiff tel: +1 857 284 3847 CF10 3AX, UK Neuroregeneration Laboratories, Center for Neuroregeneration Research, Mailman Regina Rumpel Research Center, Rm. 125, McLean email: [email protected] Hospital/Harvard Medical School, 115 Mill tel: +49 511 532 2894 Street, Belmont MA 02478, USA Institute of Neuroanatomy, OE 4140, Carl- Neuberg-Str. 1, 30625 Hannover, Germany Evan Snyder email: [email protected] Daniella Rylander tel: +1 858 646 3158 email: [email protected] Sanford-Burnham Medical Research Institute tel: +46 46 222 3418 10901 N. Torrey Pines Road, La Jolla CA, USA BMC A11, Sölvegatan 17, 22184 Lund, Sweden Ingrid Strömberg email: [email protected] tel: +46 90 786 6585 Dept of Integrative Medical Biology, Umeå University, S-901 87 Umeå, Sweden
125 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
Clive Svendsen Lachlan Thompson email: [email protected] email: [email protected] tel: +1 310 248 8560 tel: +61 3 8344 7486 8700 Beverly Blvd, AHSP A8404 Los Angeles, Howard Florey Institute, University of CA 90048, USA Melbourne, Parkville, Victoria 3010, Australia
Sarah Tabrizi Eduardo Torres email: [email protected] email: [email protected] tel: +44 203 448 4053 tel: +44 2920 774115 Dept of Neurodegenerative Disease, UCL Brain Repair Group, School of Biosciences, Institute of Neurology, Queen Square, London Cardiff University, Museum Avenue, Cardiff WC1N 3BG, UK CF10 3AX, UK
Naoki Tajiri Matthieu Trigano email: [email protected] email: [email protected] tel: +1 813 974 1666 tel: +33 6 69 41 80 33 University of South Florida Morsani College of 13 rue Matisse, 95220 Herblay, France Medicine 12901 Bruce B. Downs Blvd., MDC78 Tampa, FL 33612, USA Mark Tuszynski email: [email protected] Catherine Talbot tel: +1 858 534 8857 email: [email protected] Centre for Neural Repair, University of tel: +44 2920 875545 California San Diego, La Jolla CA 92093-0626, School of Pharmacy & Pharmaceutical USA Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, UK Pierre Vanderhaegen email: [email protected] Claudia Tamburini Institute of Interdisciplinary Research email: [email protected] (IRIBHM), University of Brussels ULB, Campus tel: +44 7554 263789 Erasme CP 602, 808 Route de Lennik, B-1070 Top floor flat 102, Llandaff Road, Cardiff CF11 Brussels, Belgium 9NN, UK Catherine Verfaille Yang D (Ted) Teng, ASNTR President email: [email protected] email: [email protected] tel: +32 16 33 02 95 tel: +1 617 525 8676 Interdepartmental Stem Cell Institute, Catholic Dept of Surgery, Brigham and Women's University of Leuven, O&N1 bus 804, Hospital, Harvard University, 221 Longwood Herestraat 49, B-3000 Leuven, Belgium Avenue, Boston MA 02115, USA Ngoc-Nga Vinh Rhian Thomas email: [email protected] email: [email protected] tel: +44 2920 875762 tel: +44 2920 874000 Brain Repair Group, School of Biosciences, School of Pharmacy and Pharmaceutical Cardiff University, Museum Avenue, Cardiff Sciences Cardiff University Redwood Building CF10 3AX, UK King Edward VII Ave, Cardiff CF10 3NB, UK
126 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
Marcella Vortruba Jordan Wright email: [email protected] email: [email protected] tel: +44 2920 870134 tel: +61 421 859592 Mitochondria & Vision Lab, Cardiff Centre for Melbourne Brain Centre, The University of Vision Sciences, College of Biomedical and Life Melbourne, Victoria 3010, Australia Sciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ Mehmet Fatih Yanik email: [email protected]; [email protected] Oi Wan Wan tel: +1 650 814 7067 email: [email protected] Massachusetts Institute of Technology, 77 tel: +46 46 222 0545 Massachusetts Avenue, Room 36-834, Neurobiology Lund University BMC, A11 221 84 Cambridge MA 02139, USA Lund Sweden Emma Yhnell Ying Wang email: [email protected] email: [email protected] tel: +44 2920 874684 tel: -83911370 Brain Repair Group, School of Biosciences, JiePing Building 116,Basic Medical School, Cardiff University, Museum Avenue, Cardiff Capital Medical University, YouAnMen CF10 3AX, UK No.10,Beijing 100069, China Ting Zhang Yuqin Wang email: [email protected] email: [email protected] tel: +86 10 83950072 tel: +44 1792 602730 719 Jichukeyan building, Capital Medical Grove Building College of Medicine Swansea University, Fengtai District, Beijing City 100069, University SA2 8PP UK China
Paul Whiting Wei-Ming Zhao email:[email protected] email: [email protected] tel: +44 1304 643485 tel: +44 7857 835252 Neusentis, a Pfizer Research Unit, The Portway John van Geest Centre for Brain Repair, Building, Granta Park Science Park, Great University of Cambridge Forvie Site, Robinson Abington, Cambridge CB1 6GS, UK Way, Cambridge CB2 0PY, UK
Hans Widmer Jens Zimmer email: [email protected] email: [email protected] tel: +41 (0)31 632 2770 tel: +45 60 113 801 Department of Neurosurgery Research Neurobiology Research University of Southern Laboratory, University of Bern, Inselspital, CH- Denmark, J. B. Winslow Vej 2, DK-5000 Odense 3010 Bern, Switzerland C, Denmark
127 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
AUTHOR INDEX The index lists all authors of the oral (O) and poster (P) presentations, the abstracts of which appear on pages 27-64 and 65-105 respectively. Abstract numbers in bold indicate the presenting author.
Acosta S, P24 Capetian P, O3 Elgstrand-Wettergren E, P25 Aime S, P22 Carr AJF, O25 Elsworth JD, P3 Ali RR, P10 Carraro U, O15 Evans AE, P6 Allen ND, P9, P38 Carta MP, 31 Faegermann E, P32 Alvarez-Buylla A, O2 Cenci MA, O27 Fahlke C, P23 Anderson J, P35 Césaro P, O23 Fahmy TM, P21 Arber C, O19, P34 Chandran S, O7 Fawcett JW, O9 Arenas E, P12 Chen L, O15 Fenelon G, O23 Avalos P, O12, O28 Chen M, O28 Feng S, O15 Azmitia L, O3 Chernykh E, O15 Fidalgo C, P30 Backofen-Wehrhahn B, O10 Choi J, O31 Fischer M, P23 Badger JL, O26, P1 Choompoo N, P4 Fjodorova M, P7 Badylak SF, P22 Coffey PJ, O25 Foltynie T, O16 Bagetta V, O27 Collier TJ, P3 Fricker RA, P8, P11 Barbuti PA, P1 Colton T, P20 Fritsch B, P16 Barclay L, O11 Coulthard E, O11 Furlanetti L, P16 Barde Y-A, O4 Crain AM, O31, P31 García J, P16, P18 Barker RA, O5, O23, P21 Cristante AF, O15 Garcia L, O12, O28 Barque N, O11 Crompton LA, O26, P1 Gardoni F, O27 Beagan J, O30 da Cruz L, O25 Geater C, P9 Ben M’Barek K, O21 Dailey T, P24 Gemma C, P33 Bernau K, P20 Dailey T, P33 Gernert M, O10, P13 Bhangal M, P8 Deda H, O15 Gey L, O10, P13 Bhatia K, O16 delli Castelli D, P22 Gill SS, O11 Bienemann A, O11 Di Luca M, O227 Gong XL, P41 Björklund A, O16, P30 Di Santo S, P29 Gonzalez-Cordero A, P10 Bjugstad KB, P3 Di Santo S, P5 Goureau O, O21 Blanchard BC, P3 Ding W, P41 Gowing G, O12, O28 Bohbot A, O15 Döbrössy MD, O3, P16, P18 Gray WP, O13 Borlongan CV, O6, P24, P33 Doctor KS, O31 Grealish S, O24, P15 Brandel M, P31 Dodiya HB, P20 Griffin SM, P11 Breger LS, P2 Dolors M, O15 Griffiths WJ, P12 Brill LM, O31 Dolphin P, O23 Grothe C, P23, P28 Brooks SP, P14, P40 Donert M, P23 Gurdon JG, O1 Brugiere P, O23 Dowd E, O22 Gurruchaga J-M, O23 Brundin P, O16 Duan W-M, O8 Gutierrez GJ, O31 Brunelli G, O15 Ducray AD, P17 Habeler W, O21 Bubak AN, P3 Duerr C, P31 Hallett PJ, O30 Buttery P, O23 Dunnett SB Halpain S, P31 Calabrese B, P31 Dunnett SB, O18, O19, P2, P7, Handreck A O10, P13 Calabresi P, O27 P14, P37, P40 Hantraye P, O14, O23 Caldwell MA, O26, P1 Effenberg A, P23 Harrison DJ, P14 Cambray S, O19 Elger DA, P13 Hawkins CP, P11
128 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
Hayes M, O30 Lane EL, P2 Nikkhah G, O3 He X, O15, P21 Latter J, O12, O28 Onose G, O15 Heimberg M, P17 Lavisse S, O23 Orädd G, P32 Hernandez-Ontiveroz D, P24 Lawrence A, O11 Orme RP, P8, P11 Heuer A, O19, P15, P38 Lelos MJ, O18 Ornelas L, O12, P20 Hoban D, O22 Lepetit H, O23 Otom A, O15 Hoffmann N, P16 Li J, O15 Özer M, P23, P28 Hou J, O31 Li M, O19, P34 Pabón MM, P24 Hruby M, P27 Li SS, P39 Palfi S, O23 Hu GZ, P41 Limousin P, O16 Pandit A, O22 Huang H, O15 Lindvall O, O16 Paradis R, O12 Huang X, O31 Ling W, P22 Parish C, P19 Hurley A, O28 Lipton SA, O31 Parmar M, O24, P15 Hvoslef-Eide M, O17 Lisci C, P30 Patel N, O11 Isacson O, O30 Lopes P, P32 Pearson R, P10 Isaksson C, P25 Löscher W, O10 Pendolino V, O27 Ishikawa H, P24, P33 Lundberg C, P25 Peschanski M, O21 Iwamuro H, O23 Lundblad M, P15 Petersen B, O10 Iwatsu K, O15 Luz M, O11 Pfisterer U, O24 Izen SC, O30 Malapira T, P33 Piccini P, O16 Jahanshahi M O16, Mall EM, P13 Picconi B, O27 Jarraya M, O21 Manfré G, P25 Pickard MR, P11 Jendelová P, P27 Mangano EN, O30 Plancheron A, O21 Jensen P, P17 Marshall C, O11 Poewe W, P18 Jeon SR, O15 Mattis VB, P20 Politis M, O16 Jin T, P22 McCarthy M, P31 Pollini D, P29 Ju RK, P39 McClung C, P31 Powner MB, O25 Kaindlstorfer C, P18 McLean JR, O30 Precious SV, O19, P38 Kaneko Y, P24, P33 Medberry CJ, P22 Price J, P27 Kang KS, O15 Mencacci N, O16 Quinn N, O16 Karová K, P27 Metcalf C, P24 Quintino L, P25 Kas A, O23 Metcalfe SM, P21 Ralph GS, O23 Kauhausen J, P19 Meyer M,P17 Ramelli AL, O23 Kefalopoulou Z, O16 Milan M, O15 Ramsden C, O25 Kelly CM, O18, O19, P4, P26, Miskin J, O23 Ratzka A, P23, P28 P38 Mitrophanous K, O23 Redmond DE Jr, P3 Kemp PJ, P9, P38 Mochizuki H, O20 Rehncrona S, O16 Kern H, O15 Modo M, P22 Rehnmark A, P32 Kidd EJ, O17, P36 Mohr E, O11 Reidling J, P20 Kim S, P22 Monville C, O21 Remy P, O23 Kingsman S, O23 Mooney L, O11 Ren XM, P41 Kirkeby A, O24, P15 Moviglia G, O15 Rinaldi F, O26 Klein A, P23, P28 Muresanu D, O15 Risner-Janiczek JR, O19 Klein RL, O8 Naylor S, O23 Roberton VH, P26 Klett M, O3 Nelander J, O24 Rodríguez TA, O19 Konya D, P35 Newland B, O22 Romanyuk N, P27 Kordower JH, P20 Nicholls F, P22 Rosser AE, O18, O19, P4, P6, Kumar A, O15 Niemann H, O10 P26, P38
129 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
Roth RH, P3 Tabrizi S, O32 Wang XM, P41 Rumpel R, P23, P28 Tajiri N, P24, P33 Wang Y, P12, P39 Rylander D, O27 Talantova M, O31 Watts C, O23 Saberi H, O15 Tamboli C, P24 Wen YJ, P39 Sahabian A, O12, P20 Tamburini C, P34 Wenning G, P18 Sahel JA, O21 Tani N, O23Taylor MV, P6 Wesemann M, P23, P28 Sareen D, O12, P20 Teng YD, P35 West E, P10 Scorer S, O23 Theofilopoulos S, P12 Whone AL, O11, P1 Seiler S, P5, P29 Thomas RS, O17, P36 Widmer HR, P5, P17, P29 Sharma A, O15 Thompson LH, O36, P19 Widner H, O16 Sharma HS, O15 Thompson LM, P20 Winkler C, P16, P18 Shelley B, O28 Tobe BTD, O31, P31 Winquist AM, P31 Shin E, P30 Torres EM, O18, P37, P7 Wolf DA, O31 Shinozuka K, P24, P33 Tran A, P20 Woolly M, O11 Sidor M, P31 TRANSEURO consortium, O5 Wright J, O36 Singec I, O31, P31 Trigano M, P37 Xi H, O15 Sladek JR, O29, P3 Tronci E, P30 Xu QY, P39 Smart MJK, O25 Tuszynski MH, O33 Xue YQ, O8 Smith GA, O30 Tyers P, P21 Yang C, O8 Snyder EY, O31, P31 Uney JB, P1 Yang Y, O21 Sowden J, P10 Vale F, P33 Yhnell E, P40 Staggenborg K, O12, O28 Vanderhaeghen P, 035 Yu D, P35 Stancampiano R, P30 Vasconcellos J, P24 Yu SK, P39 Staples M, P24 Verfaillie CM, O34 Zelaya J, O28 Stefanova N, P18 Vetrik M, P27 Zeng X, P35 Strömberg I, P32 Vinh NN, P4, P38 Zhang S, O15 Sullivan R, P33 Virel A, P32 Zhang T, P41 Sun T, O15 von Wild K, O15 Zhao JW, P21 Svendsen CN, O12, O28, P20 Wakeman DR, P20 Zhao LR, O8 Syková E, P27 Wang D, O15 Zianni E, O27
130 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
YOUR NOTES
131 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
132 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
133 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
134 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
135 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
136 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
137 XIIth International Symposium on Neural Transplantation Cardiff, Wales UK, 3rr – 6th September 2013
138 12TH International Symposium on Neural Transplantation Cardiff, Wales UK, 3rd – 6th September 2013
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