Role of Perivascular Oligodendrocyte Precursor Cells in Angiogenesis After Brain Ischemia

Background Oligodendrocyte precursor cells ( OPC s) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPC s after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPC s in the ischemic brain. Methods and Results The behavior of OPC s was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPC s after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPC s was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPC s in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA ‐seq analysis revealed that primary cultured OPC s increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPC s secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPC s. Hypoxic OPC ‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC ‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities. Conclusions Following cerebral ischemia, the phenotype of OPC s in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPC s secretome would provide a novel therapeutic option for stroke.