期刊
ANNALS OF NEUROLOGY
卷 76, 期 2, 页码 252-268出版社
WILEY
DOI: 10.1002/ana.24201
关键词
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资金
- National Institute of Health and Medical Research_INSERM
- European Leukodystrophy Association (ELA)
- French National Research Agency (ANR)
- MS Society of Canada
- program Investissements d'avenir [ANR-10-IAIHU-06]
- ELA postdoctoral fellowship
- Foundation for Medical Research (FRM)
- Paris School of the Neurosciences (ENP)
- Health Research Fund of Quebec Researcher National Award
- Killam Trust
- Public Hospital Network of Paris/Department of Neurology, Pitie-Salpetriere Hospital
Objective: Chronically demyelinated multiple sclerosis (MS) lesions are frequently characterized by scarce undifferentiated oligodendrocyte progenitor cells (OPCs), suggesting the exhaustion of a local OPC pool followed by failure of recruitment and differentiation. Stimulating prompt OPC recruitment following demyelination could improve myelin repair by providing sufficient numbers of remyelinating cells during the repair-permissive period. Understanding mechanisms that determine this process may have important therapeutic implications. We therefore investigated the role of the guidance molecule netrin-1 in OPC recruitment and central nervous system (CNS) remyelination. Methods: Netrin-1 expression was analyzed immunohistochemically in different types of MS lesions and in the murine lysolecithin model of demyelination. The influence of netrin-1 on CNS remyelination was examined using gain and loss of function experiments. Results: We show that in MS lesions, astrocytes upregulate netrin-1 expression early during demyelination and netrin-1 receptors are expressed by OPCs. In contrast, in the efficiently repairing lysolecithin model of demyelination (astrocyte-free), netrin-1 expression is absent during early phases and detected concomitant with completion of OPC recruitment. In vitro migration assays demonstrated that netrin-1 is a chemorepellent for migrating adult OPCs. In mouse lesions, antibody-mediated disruption of netrin-1 function at the peak phase of recruitment increased OPC numbers. Conversely, lentiviral-mediated induction of netrin-1 expression prior to OPC recruitment reduced the number of cells recruited and impaired remyelination. Interpretation: Our findings support the conclusion that netrin-1 expression within demyelinating MS plaques blocks OPC recruitment, which with repeated demyelinating episodes contributes to permanent remyelination failure.
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