Rethinking the Oligodendrocyte Progenitor Cell: One Cell, Many Functions

ABSTRACT Oligodendrocyte progenitor cells (OPCs) are resident progenitors and the largest cycling nonneuronal population of the central nervous system (CNS). For decades, OPCs were defined by a single output—the myelinating oligodendrocyte. However, a growing body of evidence has since revealed a cell whose functions reach well beyond myelin, raising the question of whether the OPC should be regarded as a glial cell type in its own right. In this review I examine a broader repertoire of OPC functions and their relevance to CNS health and disease, alongside myelination, remyelination and myelin maintenance. Beyond forming myelinating oligodendrocytes, OPCs tune myelination to neuronal activity, regulate neural circuits directly, influence the vasculature and blood–brain barrier and act as immune sensors and effectors. These emerging myelin‐independent functions establish OPCs as active participants in CNS physiology and pathology rather than a cell defined solely by the oligodendrocytes it produces. Finally, I consider two challenges shared across all these functions and that have, until now, been studied almost exclusively in relation to myelination: OPC heterogeneity and ageing. Whether these noncanonical functions are performed by all OPCs or by distinct subsets and inducible states and how each function is shaped across the lifespan and in pathological contexts, remains unresolved. I propose that addressing these questions is essential to understanding the relevance of these different OPC functions in health and disease.