Abstract Objective Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti–LINGO‐1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. Methods The effects of LINGO‐1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO‐1 antagonists on OPC differentiation and myelin repair. Results The data indicate that in vitro treatment with antagonists of LINGO‐1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine‐ or cuprizone‐induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. Interpretation Our studies demonstrate that LINGO‐1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO‐1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination. Ann Neurol 2009;65:304–315

Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells