TY - JOUR T1 - Pericyte-mediated tissue repair through PDGFRβ promotes peri-infarct astrogliosis, oligodendrogenesis and functional recovery after acute ischemic stroke JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0474-19.2020 SP - ENEURO.0474-19.2020 AU - Tomoya Shibahara AU - Tetsuro Ago AU - Kuniyuki Nakamura AU - Masaki Tachibana AU - Yoji Yoshikawa AU - Motohiro Komori AU - Kei Yamanaka AU - Yoshinobu Wakisaka AU - Takanari Kitazono Y1 - 2020/02/07 UR - http://www.eneuro.org/content/early/2020/02/07/ENEURO.0474-19.2020.abstract N2 - Post-stroke functional recovery can occur spontaneously during the subacute phase; however, how post-stroke fibrotic repair affects functional recovery is highly debated. Platelet derived growth factor receptor beta (PDGFRβ)-expressing pericytes are responsible for post-stroke fibrotic repair within infarct areas; therefore, we examined peri-infarct neural reorganization and functional recovery after permanent middle cerebral artery occlusion (pMCAO) using pericyte-deficient Pdgfrb+/– mice. Time-dependent reduction of infarct area sizes, i.e. repair, was significantly impaired in Pdgfrb+/– mice with recovery of cerebral blood flow in ischemic areas attenuated by defective leptomeningeal arteriogenesis and intra-infarct angiogenesis. Peri-infarct astrogliosis, accompanied by increased STAT3 phosphorylation, was attenuated in Pdgfrb+/– mice. Pericyte-conditioned medium (PCM), particularly when treated with platelet derived growth factor subunit B (PDGFB) homodimer (PDGF-BB) (PCM/PDGF-BB), activated STAT3 and enhanced the proliferation and activity of cultured astrocytes. Although peri-infarct proliferation of oligodendrocyte precursor cells (OPCs) was induced promptly after pMCAO regardless of intra-infarct repair, OPC differentiation and remyelination were significantly attenuated in Pdgfrb+/– mice. Consistently, astrocyte-conditioned medium promoted OPC differentiation and myelination, which were enhanced remarkably by adding PCM/PDGF-BB to the medium. Post-stroke functional recovery correlated well with the extent and process of intra-infarct repair and peri-infarct oligodendrogenesis. Overall, pericyte-mediated intra-infarct fibrotic repair through PDGFRβ may promote functional recovery through enhancement of peri-infarct oligodendrogenesis as well as astrogliosis after acute ischemic stroke.Significance Statement Pericyte-mediated fibrotic tissue repair is a major histological change within the infarct area during the subacute phase after ischemic stroke. Whether fibrotic repair is beneficial or detrimental to post-stroke functional recovery is highly debated. Here we demonstrate that inhibition of fibrotic repair in mice by heterozygous deletion of PDGFRβ (Pdgfrb+/–) significantly attenuates functional recovery after ischemic stroke. Pericyte-derived PDGFRβ-positive cells within the infarct area produced trophic factors that activated astrocytes, thereby enhancing peri-infarct astrogliosis. Furthermore, astrocytes, conditioned with PDGF-BB-stimulated pericyte culture medium, promoted oligodendrocyte differentiation and a myelinating response. Peri-infarct oligodendrogenesis and re-myelination within areas of astrogliosis was significantly attenuated in Pdgfrb+/– mice. Pericyte-mediated tissue repair is beneficial for post-stroke functional recovery and is a potential therapeutic target. ER -