Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy. Issue 7 (July 2021)

• Record Type: Journal Article
• Authors: Suzuki, Toshihiko; Sato, Yoshiaki; Kushida, Yoshihiro; Tsuji, Masahiro; Wakao, Shohei; Ueda, Kazuto; Imai, Kenji; Iitani, Yukako; Shimizu, Shinobu; Hida, Hideki; Temma, Takashi; Saito, Shigeyoshi; Iida, Hidehiro; Mizuno, Masaaki; Takahashi, Yoshiyuki; Dezawa, Mari; Borlongan, Cesar V; Hayakawa, Masahiro
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 41:Issue 7(2021)
• Page Start: 1707
• Page End: 1720
• Publication Date: 2021-07
• Subjects: Microglia -- Muse cells -- perinatal hypoxic ischemic encephalopathy -- Rice Vannucci model -- stage-specific embryonic antigen-3; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X20972656
• Languages: English
• ISSNs: 0271-678X

Abstract

Perinatal hypoxic ischemic encephalopathy (HIE) results in serious neurological dysfunction and mortality. Clinical trials of multilineage-differentiating stress enduring cells (Muse cells) have commenced in stroke using intravenous delivery of donor-derived Muse cells. Here, we investigated the therapeutic effects of human Muse cells in an HIE model. Seven-day-old rats underwent ligation of the left carotid artery then were exposed to 8% oxygen for 60 min, and 72 hours later intravenously transplanted with 1 × 10 4 of human-Muse and -non-Muse cells, collected from bone marrow-mesenchymal stem cells as stage-specific embryonic antigen-3 (SSEA-3)+ and −, respectively, or saline (vehicle) without immunosuppression. Human-specific probe revealed Muse cells distributed mainly to the injured brain at 2 and 4 weeks, and expressed neuronal and glial markers until 6 months. In contrast, non-Muse cells lodged in the lung at 2 weeks, but undetectable by 4 weeks. Magnetic resonance spectroscopy and positron emission tomography demonstrated that Muse cells dampened excitotoxic brain glutamatergic metabolites and suppressed microglial activation. Muse cell-treated group exhibited significant improvements in motor and cognitive functions at 4 weeks and 5 months. Intravenously transplanted Muse cells afforded functional benefits in experimental HIE possibly via regulation of glutamate metabolism and reduction of microglial activation.