Effects of sphingosine-1-phosphate receptor modulators on remyelination in multiple sclerosis: evidence from in vitro experiments, animal models and human studies.

Sphingosine-1-phosphate (S1P) receptor modulators are a class of therapeutic agents used for the treatment of multiple sclerosis (MS). There are four S1P modulators currently approved by the Food and Drug Administration/European Medical Agency (FDA/EMA): fingolimod, siponimod, ponesimod, and ozanimod. Beyond their well-established immunomodulatory properties, accumulating evidence suggests that these molecules exert direct effects on oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes, promoting myelin repair through multiple mechanisms. In vitro studies show enhanced OPC differentiation and process extension, while in vivo models demonstrate increased remyelination, improved myelin protein expression, and functional recovery. Imaging studies in people with MS suggest increased myelin repair over time. Potential mechanisms underlying the observed effects involve selective modulation of S1P receptor subtypes (particularly S1PR1, S1PR3, and S1PR5). This comprehensive review summarizes available preclinical and clinical evidence on the role of S1P modulators in remyelination in the context of MS and shows that fingolimod, siponimod and ponesimod possess emerging promise in this field.