Oligodendrocyte Precursor Cells in Demyelination Repair: Mechanisms, Crosstalk, and Therapeutic Frontiers

ABSTRACT In multiple sclerosis (MS), demyelination is often accompanied by severe motor and cognitive disability. Remyelination is the process of regenerating new myelin sheath on impaired axons, which is typically carried out by oligodendrocyte precursor cells (OPCs). During remyelination, OPC differentiation is precisely regulated by various extracellular factors and intracellular signaling pathways. Moreover, other cells in lesions interact with OPC to regulate their activities. However, remyelination usually fails in the demyelinated area, resulting in chronic lesions and an extended disease duration. In this review, we discuss: (1) the basic process of OPC mediated remyelination, including OPC activation, proliferation, recruitment and differentiation, (2) crosstalks between OPC and other glia and lymphocytes, including astrocytes, macrophages, microglia and T lymphocytes, (3) signaling pathways participate in OPC differentiation, including Wnt signaling, NOTCH signaling, Akt/Mtor signaling, ERK/MAPK signaling and BMP signaling and (4) non‐disease‐related reasons and disease‐related reasons why remyelination fails. By integrating mechanistic insights with translational challenges, our review underscores the potential of targeting OPC dynamics and microenvironmental crosstalk to develop precision therapies for demyelinating diseases. Furthermore, it identifies critical gaps in current research, advocating for combinatorial strategies that address both aging‐related barriers and pathway‐specific dysregulation to restore CNS repair capacity.