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This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. The CX3CR1/CX3CL1 Axis Drives the Migration and Maturation of Oligodendroglia in the Central Nervous System Catriona Ford Thesis Submitted for the Degree of Doctor of Philosophy The University of Edinburgh 2017 Abstract In the central nervous system, the axons of neurons are protected from damage and aided in electrical conductivity by the myelin sheath, a complex of proteins and lipids formed by oligodendrocytes. Loss or damage to the myelin sheath may result in impairment of electrical axonal conduction and eventually to neuronal death. Such demyelination is responsible, at least in part, for the disabling neurodegeneration observed in pathologies such as Multiple Sclerosis (MS) and Spinal Cord Injury. In the regenerative process of remyelination, oligodendrocyte precursor cells (OPCs), the resident glial stem cell population of the adult CNS, migrate toward the injury site, proliferate and differentiate into adult oligodendrocytes which subsequently reform the myelin sheath. Existing research indicates that OPC migration is directed by chemomigratory signals released from the site of injury and that the absence of OPCs is a feature of some MS lesions, suggesting that increased recruitment of OPCs to injury sites might improve remyelination, eventually leading to treatments of patient pathologies. I hypothesized that as yet undiscovered migration cues for OPCs might be released at sites of demyelination, diffuse through the CNS tissue, activate distal OPCs and guide them back to sites of demyelination. In this thesis, I performed bioinformatics analysis of gene expression arrays and identified upregulated cell surface receptors on OPCs activated in a cuprizone model, and upregulated secreted factors in whole lesion sites from an LPC induced MS type injury model and a Spinal Cord Injury model. I then optimised the X-celligence system for the quantification of OPC migration in response to secreted factors identified in my bioinformatics screen. By combination of these techniques with immunofluorescent staining I discovered novel expression of the cell surface receptor CX3CR1 on OPCs, increased expression of the corresponding ligand CX3CL1 in both MS type injury and Spinal Cord Injury, increased directional migration of OPCs in response to low concentrations of CX3CL1, and increased maturation of OPCs into adult oligodendrocytes at high concentrations of CX3CL1. Taken together these results propose a system in which an increasing gradient of CX3CL1 released from the site of injury directs the recruitment, then maturation of OPCs, making CX3CL1 a master regulator of OPC led CNS regeneration. Lay Summary In the brain and spinal cord, the neurons which relay electrical signals are protected and insulated by the myelin sheath which is made by support cells known as oligodendrocytes. Loss of the myelin sheath can lead to the death of neurons which prevents the brain from sending signals properly and can cause disability in conditions like Multiple Sclerosis (MS) and Spinal Cord Injury. For lost myelin to be replaced repair brain cells scattered throughout the brain and spinal cord must migrate into the injury site, change into adult oligodendrocytes and make new myelin sheaths. In conditions like MS and Spinal Cord Injury this repair process does not always work properly because the repair stem cells do not find their way to the area needing repaired. The purpose of my project was to find a way to recruit more of these repair stem cells into injury sites. By analysing online databases, I identified chemical signals released at the site of injury and studied cells cultured in a dish to find out if adding these chemical signals increased repair, stem cell migration or the maturation of repair stem cells into oligodendrocytes. I found a protein called CX3CL1 which made the repair stem cells migrate and mature more quickly and it is hoped that we might be able to develop CX3CL1 into a drug to treat MS and Spinal Cord Injury in the future. Declaration The work for this doctoral thesis was conducted at the Scottish Centre for Regenerative Medicine at the University of Edinburgh. I declare that the research described within this thesis is my own work and that this thesis was composed by myself unless otherwise specified in the text or the acknowledgements. Neither this dissertation nor part thereof has been submitted for academic merit at another educational institution. Catriona Ford, January 2017 Acknowledgements Accomplishment of the body of work which makes up this thesis would not have been possible without the support of a number of others. I would firstly like to sincerely thank my primary supervisor Professor Anna Williams for her insight, guidance and unwavering support throughout my experimental work and thesis writing. I would also like to thank my secondary supervisor Dr Simon R Tomlinson for his supervision and support throughout the bioinformatic component of the project, and my thesis committee Professor Lesley Forrester and Professor Charles ffrench- Constant. In addition, this project would not have been possible without the wit and wisdom of both past and present members of the Williams and Tomlinson labs, in particular Dr Rikesh Rajani, Elitsa Peeva, Amanda Boyd, Misuzu Hashimoto, Claire Fournier, Dr Sowmya Sekizar, Dr Eva Borger, Sonja Rittchen, Silvie Ruigrok, Thomas Carr, Dr Florian Halbritter, Dr Jonathan Manning, Alison McGarvey, Anastasia Kousa, James Ashmore and Will Bowring. I would also like to thank the Medical Research Council for funding my scholarship, and the Scottish Centre for Regenerative Medicine for hosting my project. Finally, I would also like to thank my family and friends for their constant interest (feigned or otherwise!) and encouragement and my partner Duncan Godwin, not only for his positivity and endless reassurance through the difficult times, but also for the crash courses in Java/Javascript and remote controlled Lego cars. Contents Chapter 1 - Introduction 1.1 Myelin ................................................................................................................................ 3 1.1.1 Myelin and the Propagation of Electrical Impulses ................................................ 3 1.1.2 Myelin Composition .................................................................................................. 3 1.1.3 Myelin Function ......................................................................................................... 3 1.1.4 Adult Oligodendrocytes are Unable to Regenerate ................................................ 5 1.2 Development..................................................................................................................... 5 1.2.1 Myelination in Development .................................................................................... 5 1.2.2 Oligodendrocytes are the Terminally Differentiated Progeny of Increasingly Lineage Restricted Precursors .......................................................................................... 6 1.2.3 Developmental OPCs First Arise in Late Gestation to Early Neonatal Phase ....... 6 1.2.4 CNS Patterning in Development ............................................................................... 7 1.2.5 Origins of OPCs in the Developing Spinal Cord ....................................................... 8 1.2.5.1 Historical Ventral Perspective on OPC Origins – Spinal Cord ......................... 8 1.2.5.2 Dorsal Origin of OPCs in the Spinal Cord .......................................................... 9 1.2.6 Origins of OPCs in the Developing Brain ............................................................... 12 1.2.6.1 OPCs in the Developing Brain .......................................................................... 12 1.2.6.2 OPCs Arise in Three Sequential Waves in the Developing Forebrain .......... 13 1.2.7 Origins of OPCs in the Developing Optic Nerve .................................................... 14 1.2.8 Developmental Migration of OPCs is Orchestrated by Chemomigratory Molecules ........................................................................................................................................... 16 1.3 Multiple Sclerosis ........................................................................................................... 17 1.4 Regeneration .................................................................................................................. 19 1.4.1 The Role of OPCs in the Normal Adult CNS ........................................................... 19 1.4.2 The Role of OPCs in Regeneration ......................................................................... 21
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