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.

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.

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.

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. Ann Neurol 2014;76:252–268