Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy

• Published in: Journal of cerebral blood flow and metabolism Vol. 41; no. 7; pp. 1707 - 1720
• Main 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
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.07.2021
• Subjects: Original; Rice Vannucci model; perinatal hypoxic ischemic encephalopathy; Muse cells; stage-specific embryonic antigen-3; Microglia
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X20972656

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 × 104 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.