Spinal cord injury (SCI) induces a centralized fibrotic scar surrounded by a reactive glial scar at the lesion site. The origin of these scars is thought to be perivascular cells entering lesions on ingrowing blood vessels and reactive astrocytes, respectively. However, two NG2-expressing cell populations, pericytes and glia, may also influence scar formation. In the periphery, new blood vessel growth requires proliferating NG2 pericytes; if this were also true in the CNS, then the fibrotic scar would depend on dividing NG2 pericytes. NG2 glial cells (also called oligodendrocyte progenitors or polydendrocytes) also proliferate after SCI and accumulate in large numbers among astrocytes in the glial scar. Their effect there, if any, is unknown. We show that proliferating NG2 pericytes and glia largely segregate into the fibrotic and glial scars, respectively; therefore, we used a thymidine kinase/ganciclovir paradigm to ablate both dividing NG2 cell populations to determine whether either scar was altered. Results reveal that loss of proliferating NG2 pericytes in the lesion prevented intralesion angiogenesis and completely abolished the fibrotic scar. The glial scar was also altered in the absence of acutely dividing NG2 cells, displaying discontinuous borders and significantly reduced GFAP density. Collectively, these changes enhanced edema, prolonged hemorrhage, and impaired forelimb functional recovery. Interestingly, after halting GCV at 14 d postinjury, scar elements and vessels entered the lesions over the next 7 d, as did large numbers of axons that were not present in controls. Collectively, these data reveal that acutely dividing NG2 pericytes and glia play fundamental roles in post-SCI tissue remodeling. Spinal cord injury (SCI) is characterized by formation of astrocytic and fibrotic scars, both of which are necessary for lesion repair. NG2 cells may influence both scar-forming processes. This study used a novel transgenic mouse paradigm to ablate proliferating NG2 cells after SCI to better understand their role in repair. For the first time, our data show that dividing NG2 pericytes are required for post-SCI angiogenesis, which in turn is needed for fibrotic scar formation. Moreover, loss of cycling NG2 glia and pericytes caused significant multicellular tissue changes, including altered astrocyte responses and impaired functional recovery. This work reveals previously unknown ways in which proliferating NG2 cells contribute to endogenous repair after SCI.

Oligodendrocytes are specialized glial cells that myelinate central nervous system (CNS) axons. Historically, it was believed that the primary role of myelin was to compactly ensheath axons, providing the insulation necessary for rapid signal conduction. However, mounting evidence demonstrates the dynamic importance of myelin and oligodendrocytes, including providing metabolic support to neurons and regulating axon protein distribution. As such, the development and maintenance of oligodendrocytes and myelin are integral to preserving CNS homeostasis and supporting proper functioning of widespread neural networks. Environmental signals are critical for proper oligodendrocyte lineage cell progression and their capacity to form functional compact myelin; these signals are markedly disturbed by injury to the CNS, which may compromise endogenous myelin repair capabilities. This review outlines some key environmental factors that drive myelin formation during development and compares that to the primary factors that define a CNS injury milieu. We aim to identify developmental factors disrupted after CNS trauma as well as pathogenic factors that negatively impact oligodendrocyte lineage cells, as these are potential therapeutic targets to promote myelin repair after injury or disease.