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Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models.

TitleInsufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models.
Publication TypeJournal Article
Year of Publication2013
AuthorsBoyd A, Zhang H, Williams AC
JournalActa Neuropathol
Volume125
Issue6
Pagination841-59
Date Published2013 Jun
ISSN1432-0533
KeywordsAdult, Aged, Aged, 80 and over, Animals, Case-Control Studies, Cell Movement, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Multiple Sclerosis, Neural Stem Cells, Neuropilin-1, Oligodendroglia, Regeneration, Semaphorins
Abstract

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1.

DOI10.1007/s00401-013-1112-y
Alternate JournalActa Neuropathol.
PubMed ID23595275
PubMed Central IDPMC3661931
Grant ListG-0909 / / Parkinson's UK / United Kingdom
/ / Wellcome Trust / United Kingdom