Role of Hypoxic OPC in Angiogenesis
Kishida, Natsue Kyoto University
Maki, Takakuni Kyoto University
Takagi, Yasushi Kyoto University|Tokushima University Tokushima University Educator and Researcher Directory
Yasuda, Ken Kyoto University
Kinoshita, Hisanori Kyoto University
Ayaki, Takashi Kyoto University
Noro, Takayuki Kyoto University
Kinoshita, Yusuke KAN Research Institute
Ono, Yuichi KAN Research Institute
Kataoka, Hiroharu Kyoto University
Yoshida, Kazumichi Kyoto University
Lo, Eng H. Massachusetts General Hospital|Harvard Medical School
Arai, Ken Massachusetts General Hospital|Harvard Medical School
Miyamoto, Susumu Kyoto University
Takahashi, Ryosuke Kyoto University
Background－Oligodendrocyte precursor cells (OPCs) 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 OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain.
Methods and Results－The behavior of OPCs 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 OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs 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 OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. 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 OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke.
Journal of the American Heart Association
The American Heart Association
© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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