Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: the more, the merrier?

Promoting remyelination to prevent/reduce neurodegeneration in patients with multiple sclerosis (MS) is a major therapeutic goal. The longstanding view that the block of oligodendrocyte progenitor cell (OPC) differentiation in MS lesions is the leading cause of remyelination failure has inspired the scientific community to focus primarily on OPC differentiation-promoting compounds as pro-remyelinating agents. Yet, these strategies have been challenged by findings that active MS lesions contain surviving oligodendrocytes that may contribute to remyelination, while many chronic lesions contain low numbers of oligodendroglial cells. In addition, clinical trials using differentiation-stimulating drugs have shown limited efficacy. Thus, a strategic shift in the design of potential remyelination-promoting therapies may be required to achieve significant clinical benefits, which calls for a careful reconsideration of the mechanisms underlying remyelination failure in MS. Here, we argue that both the rate and the efficacy of OPC recruitment are fundamental determinants of remyelination, and that stimulating this process in MS may be crucial to achieve myelin regeneration. We first review different types of MS lesions in early and chronic MS, with a particular focus on OPCs and surviving oligodendrocytes. Based on the neuropathological findings and results obtained using models of demyelination, we make the case that OPC differentiation block in chronic MS is likely the consequence of defective OPC recruitment during earlier phases of the disease, because (i) if the recruitment is too slow, OPCs reach the axons after what we define as 'remyelination-permissive window', and thus remain undifferentiated; and (ii) if the recruitment is inefficient, OPC density in the lesions remains below the threshold required for differentiation. Importantly, we highlight that OPC proliferation in MS lesions is scarce, which strongly suggests that repeated episodes of demyelination/remyelination (OPC differentiation) will deplete the lesional OPC pool unless perilesional OPCs are recruited. We also point out that surviving mature oligodendrocytes in a subtype of early MS lesions may actually prevent the recruitment of OPCs. Because it has been suggested that OPC-mediated remyelination may be more efficient than that by surviving oligodendrocytes, we suggest that stimulating OPC recruitment during active disease should benefit remyelination in multiple types of lesions, including those with spared oligodendrocytes. Finally, we review molecular determinants of OPC recruitment and suggest a potential therapeutically-relevant strategy to increase this process in patients with MS.