iPSC-derived mesenchymal stem cells attenuate cerebral ischemia-reperfusion injury by inhibiting inflammatory signaling and oxidative stress

Masafumi Arakawa; Yuki Sakamoto; Yoshitaka Miyagawa; Chikako Nito; Shiro Takahashi; Yuko Nitahara-Kasahara; Satoshi Suda; Yoshiyuki Yamazaki; Mashito Sakai; Kazumi Kimura; Takashi Okada

doi:10.1016/j.omtm.2023.07.005

iPSC-derived mesenchymal stem cells attenuate cerebral ischemia-reperfusion injury by inhibiting inflammatory signaling and oxidative stress

Mol Ther Methods Clin Dev. 2023 Jul 15:30:333-349. doi: 10.1016/j.omtm.2023.07.005. eCollection 2023 Sep 14.

Authors

Masafumi Arakawa^{1

2}, Yuki Sakamoto¹, Yoshitaka Miyagawa², Chikako Nito^{1

3}, Shiro Takahashi^{1

2}, Yuko Nitahara-Kasahara⁴, Satoshi Suda¹, Yoshiyuki Yamazaki², Mashito Sakai², Kazumi Kimura¹, Takashi Okada⁴

Affiliations

¹ Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
² Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
³ Laboratory for Clinical Research, Collaborative Research Center, Nippon Medical School, Tokyo, Japan.
⁴ Division of Molecular and Medical Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Abstract

Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) hold great promise as a cell source for transplantation into injured tissues to alleviate inflammation. However, the therapeutic efficacy of iMSC transplantation for ischemic stroke remains unknown. In this study, we evaluated the therapeutic effects of iMSC transplantation on brain injury after ischemia-reperfusion using a rat transient middle cerebral artery occlusion model and compared its therapeutic efficacy with that of bone marrow mesenchymal stem cells (BMMSCs). We showed that iMSCs and BMMSCs reduced infarct volumes after reperfusion and significantly improved motor function on days 3, 7, 14, 28, and 56 and cognitive function on days 28 and 56 after reperfusion compared with the vehicle group. Furthermore, immunological analyses revealed that transplantation of iMSCs and BMMSCs inhibited microglial activation and expression of proinflammatory cytokines and suppressed oxidative stress and neuronal cell death in the cerebral cortex at the ischemic border zone. No difference in therapeutic effect was observed between the iMSC and BMMSC groups. Taken together, our results demonstrate that iMSC therapy can be a practical alternative as a cell source for attenuation of brain injury and improvement of neurological function because of the unlimited supply of uniform therapeutic cells.

Keywords: BMMSC; MSC; focal cerebral ischemia model rats; iMSC; iPSC; intravenous administration; ischemic stroke; mesenchymal stem cell; mesenchymal stromal cell; stem cell therapy.