In multiple sclerosis (MS), the presence of demyelinating plaques has concentrated researchers' minds on the role of the oligodendrocyte in its pathophysiology. Recently, with the rediscovery of early and widespread loss of axons in the disease, new emphasis has been put on the role of axons and axon-oligodendrocyte interactions in MS. Despite the fact that, in 1904, Müller claimed that MS was a disease of astrocytes, more recently, astrocytes have taken a back seat, except as the cells that form the final glial scar after all hope of demyelination is over. However, perhaps it is time for the return of the astrocyte to popularity in the pathogenesis of MS, with recent reports on the dual role of astrocytes in aiding degeneration and demyelination, by promoting inflammation, damage of oligodendrocytes and axons, and glial scarring, but also in creating a permissive environment for remyelination by their action on oligodendrocyte precursor migration, oligodendrocyte proliferation, and differentiation. We review these findings to try to provide a cogent view of astrocytes in the pathology of MS.

The presence of demyelinated plaques in the central nervous system is the hallmark of multiple sclerosis (MS). Some plaques remyelinate but others do not, leaving permanent damage. The reasons for this failure of repair are many, but one possible reason is the lack of migration of oligodendrocyte precursor cells to the lesion. The guidance molecules Semaphorin 3A and 3F, already known to direct oligodendroglial migration in development, may also be active in controlling oligodendrocyte precursor cell migration in MS, and hence may determine the ability of plaques to remyelinate. Here, in MS tissue and an experimental model of demyelination, we demonstrate a local source of these molecules around active demyelinating lesions, but not chronic plaques. We also provide evidence for their up-regulation at a distance from the lesion, in the neuronal cell bodies corresponding to the demyelinated axons. We propose that both of these mechanisms influence remyelination.

Oligodendrocyte precursor cells, which persist in the adult central nervous system, are the main source of central nervous system remyelinating cells. In multiple sclerosis, some demyelinated plaques exhibit an oligodendroglial depopulation, raising the hypothesis of impaired oligodendrocyte precursor cell recruitment. Developmental studies identified semaphorins 3A and 3F as repulsive and attractive guidance cues for oligodendrocyte precursor cells, respectively. We previously reported their increased expression in experimental demyelination and in multiple sclerosis. Here, we show that adult oligodendrocyte precursor cells, like their embryonic counterparts, express class 3 semaphorin receptors, neuropilins and plexins and that neuropilin expression increases after demyelination. Using gain and loss of function experiments in an adult murine demyelination model, we demonstrate that semaphorin 3A impairs oligodendrocyte precursor cell recruitment to the demyelinated area. In contrast, semaphorin 3F overexpression accelerates not only oligodendrocyte precursor cell recruitment, but also remyelination rate. These data open new avenues to understand remyelination failure and promote repair in multiple sclerosis.