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Evaluation of the Stimulatory Effects of EBC-46 on Dermal Fibroblast And Evaluation of the Stimulatory Effects of EBC-46 on Dermal Fibroblast and Keratinocyte Wound Healing Responses in Vitro and Correlation to Preferential Healing in Vivo Rachael Louise Moses BSc, MSc Thesis presented for the degree of Doctor of Philosophy Stem Cells, Wound Repair & Regeneration, Oral and Biomedical Sciences, Cardiff Institute of Tissue Engineering & Repair (CITER), School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK August, 2016 Dedication I would like to dedicate this thesis to my Mum, you have been an inspiration to me and given me every opportunity. I am truly thankful for your unconditional love and support, making this PhD possible. Thank you for always being there; I love you. ii Acknowledgements Firstly, I would like to give utmost thanks and appreciation to my two supervisors, Dr Ryan Moseley and Dr Robert Steadman. You have provided invaluable expertise, support, encouragement and enthusiasm throughout my project; I have thoroughly enjoyed this project. I have greatly appreciated your guidance and encouragement of my future career in research. In addition, I am hugely grateful to all who have assisted me and provided support from the School of Dentistry, Institute of Nephrology and Tenovus Building. Particular thanks go to Dr Adam Midgeley, who has provided vital support and advice on experimental procedures and subsequent analysis. I would like to thank Professor Rachel Errington, Dr Rachel Howard-Jones and Marie Wiltshire, their assistance and knowledge on flow cytometry procedures and the specialised analysis software was greatly appreciated. I would also like to thank the technical team at the School of Dentistry; who have all contributed to the successful running of the department, along with providing equipment expertise and knowledge. Additionally, I would like to express huge thanks to Dr Glen Boyle and Professor Peter Parsons, for allowing me the opportunity to perform Microarray analysis at Queensland Institute of Medical Research (QIMR), along with crucial training on undertaking these studies, and access and training on the specialised analysis software. I would like to thank the rest of the department at QIMR for graciously welcoming me and providing support and friendship, in particular Carly, Pei, Tash, Jacinta, Jenny and Vaish. I have been lucky to work with a number of great colleagues and friends in the School of Dentistry, who have provided scientific support, brilliant friendships, great humour; and personal support and encouragement, especially on those night shifts with cell cycle analysis! I would like to thank my friends, Nic, Rhi, Châni, Jen, Liv, Karina and Shannon, who have been there for me throughout this project, providing fantastic friendships and unlimited support. This project was funded by QBiotics Ltd., and I would like to take this moment to thank Dr Paul Reddell and Dr Victoria Gordon for giving me this wonderful opportunity to undertake a research project that I have thoroughly loved. I am also grateful for the funding received by CITER, enabling my research travel to QIMR, giving me an amazing experience and obtaining essential data. Finally, I would like to express heartfelt thanks to my wonderful family, in particular my Mum, Steve and grandparents; you have provided unlimited and unwavering support, encouragement and love throughout my project, keeping me somewhat sane! You have been there for me at every stage; I love you all very much and greatly appreciate all that you have done for me. iii Abstract The novel epoxy-tiglianes, EBC-46 and ‘lesser activity’ EBC-211, are sourced from seeds of the Fountain’s Blushwood Tree (Fontainea picrosperma), indigenous to Queensland Tropical Rainforest. Australian biotechnology company, QBiotics Ltd., has demonstrated that EBC-46 stimulates exceptional dermal wound healing responses in vivo, following cancer treatment and tumour destruction in domesticated animals. Consequently, QBiotics is developing EBC-46 as a veterinary anti-cancer pharmaceutical and performing human clinical trials. However, little is known on how EBC-46 induces its exceptional healing effects, manifested as accelerated wound re-epithelialisation, closure and reduced scarring. This study aimed to elucidate how EBC-46 and EBC-211 mediates these exceptional wound healing effects in vitro, through analysis of HaCaT keratinocyte and dermal fibroblast/myofibroblast genotypic and phenotypic responses, following epoxy- tigliane treatment (0.001-100µg/ml). A number of key wound healing responses were assessed, including proliferation, cell cycle progression, scratch wound repopulation; and transforming growth factor-β1 (TGF-β1)-driven, fibroblast- myofibroblast differentiation. Studies demonstrated that both EBC-46 and EBC-211 induced fibroblast and HaCaT cytotoxicity at 100µg/ml. EBC-46 and EBC-211 (0.001-10µg/ml) significantly retarded fibroblast proliferation and delayed S/G2 cell cycle transition, but exerted no significant effects on fibroblast migratory responses. Although EBC-46 had no effects on α-smooth muscle actin (α-SMA) expression, stress fibre organization and myofibroblast formation (0.001-0.01µg/ml and 1-10µg/ml), EBC-46 significantly inhibited α-SMA expression and stress fibre formation at 0.1µg/ml, with cells retaining normal fibroblast morphologies. EBC-211 induced similar effects at 10µg/ml. Both EBC-46 and EBC-211 (0.001-10µg/ml) stimulated significant HaCaT proliferation, G1/S and S/G2 cell cycle transitions; and accelerated scratch wound repopulation, even with mitomycin C. Microarray analysis and protein level validation, identified numerous differentially expressed genes in epoxy-tigliane- treated, HaCaTs. Up-regulated genes included certain keratins and others associated with promoting cell cycle progression, proliferation and migration. Down-regulated genes included other keratins and genes associated with inhibiting cell cycle progression and proliferation, including certain cytokines and chemokines. This study has provided evidence to explain the enhanced re-epithelialisation and reduced scarring responses observed in epoxy-tigliane-treated skin. Furthermore, it highlights the potential of epoxy-tiglianes as novel therapeutics for impaired dermal wound healing and excessive scarring situations. iv Patents, Prizes and Presentations Research-Related Patents Filed To Date Methods and Compositions for Wound Healing. Inventor on the following Patents in collaboration with QBiotics Ltd. and collaborators at the QIMR Berghofer Medical Research Institute (Queensland, Australia), relating to the application of epoxy-tigliane compounds, such as EBC-46 and EBC-211, in the promotion of dermal wound healing and reduced scarring:- AU20140253608, CA2909653, CN105308052, EA201591996, EP2986615, KR20160023651, PH12015502405, SG11201508588X, US2016068499; and WO201416935. Conferences Prizes Young Investigators’ Poster Prize. 28th Annual Postgraduate Research Day, Cardiff University, UK (November, 2013). Poster Prize. European Tissue Repair Society Annual Conference, Edinburgh, UK (September, 2014). Guest Speaker Identification of gene expression profiles underlying preferentially stimulated keratinocyte wound healing responses and re-epithelialisation by novel epoxy- tigliane pharmaceuticals. Wound Healing: Collaboration and Innovation for Health and Wealth. Cardiff Institute of Tissue Engineering & Repair (CITER), Cardiff University, UK (February, 2016). Other Presentations Directly Related to the Contents of This Thesis 1. Contrasting stimulatory effects of EBC-46 on dermal fibroblast and keratinocyte wound healing responses in vitro. Moses RL, Boyle GM, Reddell P, Steadman R, Moseley R. Proceedings of the 28th Annual Postgraduate Research Day, 55. Wales College of Medicine, Cardiff University, Cardiff, UK (November, 2013). v 2. Preferential stimulation of keratinocyte proliferation and migratory responses by novel tigliane pharmaceuticals contribute to enhanced wound re-epithelialisation. Moses RL, Reddell P, Steadman R, Moseley, R. European Tissue Repair Society Annual Conference, Edinburgh, UK (September, 2014). Wound Repair and Regeneration (2014), 22: A92. 3. Preferential stimulation of keratinocyte proliferation and migratory responses by novel tigliane pharmaceuticals contribute to enhanced wound re-epithelialisation. Moses RL, Reddell P, Steadman R, Moseley, R. Proceedings of the 12th Cardiff Institute of Tissue Engineering and Repair (CITER) Scientific Meeting, P21. Stradey Park Hotel, Llanelli, UK (September, 2014). 4. Pharmaceutical evaluation of novel tigliane compounds as modulators of dermal fibroblast-myofibroblast differentiation, scar tissue resolution and fibrosis; and elucidation of their underlying mechanisms of action. Dally J, Moses RL, Midgley AC, Reddell PW, Steadman R, Moseley R. Proceedings of the 1st Sêr Cymru (Life Sciences Research Network Wales) Annual Scientific Meeting, P4. St David’s Hotel, Cardiff, UK (December, 2014). 5. Epoxy-tiglianes modulate dermal fibroblast-myofibroblast wound healing responses and reduce scarring. Dally J, Moses RL, Midgley AC, Howard-Jones RA, Errington RJ, Reddell PW, Steadman R, Moseley R. British Society for Oral and Dental Research Annual Meeting, Cardiff, UK (September, 2015). Journal of Dental Research (2015), 94B: 137. 6. Epoxy-tiglianes stimulate keratinocyte proliferative and migratory responses, enhancing wound re-epithelialisation. Moses RL, Boyle GM, Reddell P, Steadman R, Moseley R. British Society for Oral and Dental Research
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