Remyelination in multiple sclerosis The Williams group is interested in how oligodendrocytes and myelin are maintained in the brain and spinal cord in health and how this changes in disease, with a focus on human neuropathology, particularly multiple sclerosis and cerebral small vessel disease.In the brain and spinal cord, nerves are covered by an insulating sheath of membrane called a myelin sheath. This allows fast transmission of electrical impulses and protects and maintains the nerve. In multiple sclerosis (MS), patches of demyelination occur, where these myelin sheaths are damaged and stripped off the nerve. This causes neurological symptoms such as paralysis, sensory changes and blindness. Replacement of these myelin sheaths (remyelination) can happen in MS, which can restore nerve function. This is generally inefficient, and often a scar forms instead, causing a long-term problem for the patient. Remyelination is carried out in part by by oligodendrocyte precursor cells which are attracted to the damaged area, make contact with nerves, mature and form myelin sheaths to replace those that are damaged. A failure of remyelination can occur with a problem at any one of these steps. If we can understand the mechanisms of each step, we may be able to manipulate them to improve the efficiency of remyelination. Professor Anna Williams Group Leader Contact details Website: Personal Profile Work: 0131 651 9500 Email: anna.williams@ed.ac.uk Image Dr Anna Williams with her research group Research summaryWe know that oligodendrocytes in the brain are heterogeneous, suggesting that different types have different functions and that the proportion of these types is skewed in MS compared to control human brains. This may suggest that the efficiency of remyelination in the context of such diseases may be different due to this skew and that righting this difference may help remyelination.We want to understand why remyelination fails in Multiple Sclerosis, why neurodegeneration occurs and to improve the efficiency of remyelination.To study this we use in vitro and ex vivo cultures from rodents and use human ES-derived cells, human post mortem tissue and in vivo rodent and zebrafish models. We seek to understand better the remyelination process, and find targets to be able to manipulate it, using both candidate and screening approaches. We manipulate levels of molecules of interest with recombinant proteins, viral transduction and using transgenic animals. Oligodendrocytes are important in other diseases besides MS, and we also study cerebral small vessel disease (SVD) which is common, important as a cause of dementia and stroke, yet relatively understudied. Here, we have recently discovered that dysfunctional endothelial cells are the key problem, secreting molecules preventing maturation of oligodendrocyte precursor cells into mature myelinating oligodendrocytes, causing white matter vulnerability. We have uncovered genetic changes which provoke endothelial cell dysfunction and cause SVD in a rodent model and are associated with the disease in humans. Reversing this endothelial dysfunction can reverse the pathology in a rat model. We want to better understand how dysfunctional endothelial cells affect oligodendroglia and myelin, causing the symptoms of the disease and how to reverse it.To do this we use in vitro and ex vivo cultures from humans and rodents, human and rodent post mortem tissue and in vivo rat models, manipulating pathology using drugs, viruses and molecular biology techniques, imaging at light and electron microscopy level. Current research interests1) Understanding mechanisms of remyelination in Central Nervous System (CNS) repair. We investigate a) which signals in the oligodendrocyte precursor cell (OPC) microenvironment direct their activation, migration and maturation for repair, b) how OPCs themselves can be manipulated to ensure more efficient repair c) how OPCs interact with other cells, including axons via synapses in the context of demyelination and remyelination, using a hierarchy of in vitro and in vivo models and d) how oligodendroglia are functionally heterogeneous, how this alters in disease and how we can model this in the lab. 2) Understanding mechanisms of cerebral small vessel disease (SVD). We investigate a) the crosstalk between endothelial cells and oligodendroglia in health and in the context of small vessel disease in humans and animal models, b) how dysfunctional endothelial cells which are dysfunctional change at the ultrastructural and functional level, c) whether we can better model this in a rat model of SVD, and d) different drugs that may aid SVD to test if and how they work, aiming to better understand the disease and improve therapies. Knowledge exchangeWe are involved in MS Society UK events, Science Festivals, teaching in schools and to teachers, art workshops and much more!Publications Publications Group MembersKarl Baldacchino (PhD Student)Nadine Bestard Cuche (Postdoctoral Research Assistant)Rana Fetit (Postdoctoral Research Fellow)Kellie Horan (PhD Student)Ronja Kremer (PhD Student)Kelly Panichnantakul (PhD Student)Rebecca Robertson (PhD Student)Daniel Ruiz Gabarre (Postdoctoral Research Fellow)Rebecca Smith (Postdoctoral Research Fellow)Julia van de Korput (PhD Student)Funders2024-2027: Progressive MS Alliance project grant - Neuronal mitochondria in MS – co-PI - £600k2024-2026: Biogen post doc grant – How does demyelination and remyelination affect axons? - £200k2023-2026: BBSRC project grant - Tools for oligodendrocyte research – PI - £660k2023-2028: UKDRI – SVD grant – CoI - £2.7 million2021-2026: MS Society UK Centre award - Co-applicant, £1.85 million.2020-2022: Roche Postdoctoral fellowship £300k2019-2022: MRC/MS Society UK - Do adult human oligodendrocytes remyelinate poorly and can we change this to better treat progressive multiple sclerosis? £600k2018-2022: Dementia Research Initiative funding (co-applicant)2018-2020: Roche Transcriptomics in MS brain ~£600k2018-2020 MRC funding for Human Cell Atlas project – Human oligodendrocyte heterogeneity £450k2017-2019: MRC Research Grant, “Transplantation of "super-OPCs" to improve central nervous system remyelination” £300k2016-2019: MS Society project grant, “Is Fractalkine (CX3CL1) a master regulator of remyelination in MS? £254k2013-2018: MRC UK Regenerative Medicine Platform - Exploring the Stem Cell Niche Hub - Co-applicant, with Hub receiving £5.6 million.2016-2017: Alzheimer’s Research UK Pilot Grant, Three-dimensional modelling of endothelial cell dysfunction in cerebral small vessel disease. £50k2015-2017: GSK - CNS slice cultures as a tool for remyelination research – £350k2015-2017: Sanofi-Genzyme - Identification of selective and potent inhibitors of the Semaphorin 3A Receptor Neuropilin-1 interaction on oligodendrocyte precursor cells to promote remyelination in Multiple Sclerosis2014-2017: Scottish Senior Fellowship – May 2013-2017 £330k CSO - Targeting OPC migration towards remyelination therapies in multiple sclerosis - £95k. 2015-2016: MS society innovative grant - Optogenetic cell ablation in a focal CNS demyelination model in slice cultures – £40k2008-2013: Wellcome Trust Intermediate Fellowship - Semaphorins in the control of remyelination in multiple sclerosis – £824,7952011-2012: Co-applicant for CSO grant with Prof. Steve Anderton - Probing regulatory T cells in multiple sclerosis brain - £165kCollaboratorsProfessor Goncalo Castelo-Branco, Karolinska InstituteProfessor Charles ffrench-Constant, University of East AngliaDr Veronique Miron, University of TorontoProfessor Joanna Wardlaw, University of EdinburghProfessor Colin Smith, University of EdinburghProfessor Siddharthan Chandran, University of EdinburghProfessor David Lyons, University of EdinburghProfessor Steve Pollard, University of EdinburghDr Don Mahad, University of EdinburghDr Lorraine Work, University of GlasgowProfessor Stuart Allan, University of Manchester This article was published on 2024-02-26
