1 Department of Neurology Graduate School of Medicine Kyoto University Kyoto Japan.
2 Department of Neurosurgery Graduate School of Medicine Kyoto University Kyoto Japan.
J Am Heart Assoc. 2019 May 7;8(9):e011824. doi: 10.1161/JAHA.118.011824.
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.
少突胶质前体细胞（OPC）通过多种方式调节神经元、神经胶质和血管系统，并表现出表型异质性，超出了其作为成熟少突胶质细胞储备库的作用。然而，脑缺血后 OPC 的详细表型变化在很大程度上仍不清楚。在此，我们旨在研究反应性 OPC 在缺血性脑损伤中的作用。
我们在体内短暂性大脑中动脉闭塞缺血性中风模型中评估了 OPC 的行为。对于体外实验，使用原代大鼠 OPC 培养物研究了 OPC 在氧葡萄糖剥夺后的表型变化。此外，我们在体内大脑中动脉闭塞模型中评估了缺氧 OPC 的治疗潜力。在大脑中动脉闭塞模型中，皮质内的血管周 OPC 与脑卒中后血管生成一起增加。体内 RNA-seq 分析显示，原代培养的 OPC 在氧葡萄糖剥夺后增加了许多促血管生成因子的基因表达。与常氧 OPC 相比，缺氧 OPC 分泌了更多的促血管生成因子，如血管内皮生长因子和血管生成素-1。缺氧 OPC 衍生的条件培养基增加了内皮细胞的活力和管形成。体内研究还表明，从大脑中动脉闭塞后 2 天开始连续 5 天给予缺氧 OPC 条件培养基治疗可促进脑卒中后血管生成，减轻梗死体积并改善功能障碍。
脑缺血后，大脑皮质中 OPC 的表型从实质亚型转变为血管周亚型，从而促进血管生成。缺氧 OPC 分泌组的最佳利用为中风提供了一种新的治疗选择。
