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

Toshihiko Suzuki, Yoshiaki Sato, Yoshihiro Kushida, Masahiro Tsuji, Shohei Wakao, Kazuto Ueda, Kenji Imai, Yukako Iitani, Shinobu Shimizu, Hideki Hida, Takashi Temma, Shigeyoshi Saito, Hidehiro Iida, Masaaki Mizuno, Yoshiyuki Takahashi, Mari Dezawa, Cesar V. Borlongan, Masahiro Hayakawa

Research output: Contribution to journalArticlepeer-review

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 × 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.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Microglia
  • Muse cells
  • Rice Vannucci model
  • perinatal hypoxic ischemic encephalopathy
  • stage-specific embryonic antigen-3

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Intravenously delivered multilineage-differentiating stress enduring cells dampen excessive glutamate metabolism and microglial activation in experimental perinatal hypoxic ischemic encephalopathy'. Together they form a unique fingerprint.

Cite this