NG2‐Glia in Central Nervous System Following Injury: From Pathological Involvement to Repair Potential

Abstract

ABSTRACT Background Central nervous system (CNS) injury remains a severe neurological condition with limited regenerative capacity. NG2‐glia are abundant and functionally versatile glial cells that have attracted increasing attention in CNS repair research. However, their roles are complex and context‐dependent, ranging from early pathological involvement to later reparative potential, and a systematic synthesis of this temporal dichotomy is lacking. Method We systematically searched PubMed and Web of Science from inception to 2026 using combinations of keywords including “NG2‐glia,” “NG2 cells,” “oligodendrocyte precursor cells,” “OPCs,” and “CNS injury.” Additional references were identified by manual screening of reference lists. We prioritized mechanistic and therapeutic studies published within the last 10 years, while foundational discoveries were included for historical context. Results This review establishes that NG2‐glia exhibit a time‐dependent dual role after CNS injury. In the early stage (hours to days), they rapidly proliferate, migrate to the lesion, and secrete chondroitin sulfate proteoglycans (CSPGs), forming a chemical and physical barrier that inhibits axonal regeneration and may facilitate neuropathic pain. In the middle‐to‐late stages (days to weeks/months), they shift toward repair functions, including remyelination via differentiation into oligodendrocytes, neuronal trans‐differentiation (primarily under forced reprogramming), and anti‐inflammatory/neuroprotective effects through interactions with microglia, astrocytes, and neurons. Their fate is determined by intrinsic factors (age, heterogeneity) and extrinsic microenvironmental signals (damage‐associated molecules, cytokines, and signaling pathways such as Wnt/β‐catenin and TGF‐β2). Therapeutically, diverse strategies—including CB1 receptor agonists to promote remyelination, chondroitinase ABC to neutralize CSPG inhibition, and SOX2/NeuroD1‐based reprogramming to generate functional neurons—have shown preclinical promise, yet significant translational gaps remain, including poor endogenous neurogenesis, constitutive differentiation limitations, and safety concerns. Conclusion and Perspective Targeting NG2‐glia offers a novel avenue for CNS repair, but successful interventions must be precisely timed and stage‐specific rather than unregulated promotion or inhibition. This review proposes an analytical framework of “time‐dependent dual roles” to reconcile the contradictory functions of NG2‐glia and highlights critical future directions, including deciphering regional heterogeneity, elucidating the molecular switches that govern state transitions, validating the functional integration of reprogrammed neurons, and bridging the bench‐to‐bedside divide. A deeper understanding of the regulatory logic underlying NG2‐glia plasticity will inform next‐generation precision therapies for CNS injuries.