Intravenous administration of human Muse cells recovers blood flow in a mouse model of hindlimb ischemia

Yusuke Hori; Tomoya Kitani; Kenji Yanishi; Takaomi Suga; Masaya Kogure; Tetsuro Kusaba; Yoshihiro Kushida; Mari Dezawa; Satoaki Matoba

doi:10.3389/fcvm.2022.981088

Intravenous administration of human Muse cells recovers blood flow in a mouse model of hindlimb ischemia

Front Cardiovasc Med. 2022 Nov 11:9:981088. doi: 10.3389/fcvm.2022.981088. eCollection 2022.

Authors

Yusuke Hori¹, Tomoya Kitani¹, Kenji Yanishi¹, Takaomi Suga¹, Masaya Kogure¹, Tetsuro Kusaba², Yoshihiro Kushida³, Mari Dezawa³, Satoaki Matoba¹

Affiliations

¹ Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
² Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
³ Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Abstract

Cell-based therapies hold great promise for the treatment of peripheral arterial disease (PAD), especially in patients presenting with severe limb ischemia, although the optimal strategy remains to be explored. In this study, we evaluated the therapeutic effect of intravenous administration of human Muse cells, a unique subpopulation of mesenchymal stem cells (MSC), using a mouse model of hindlimb ischemia (HLI) without an immunosuppressant. Compared with the phosphate buffered saline (PBS) or non-Muse MSC groups, the Muse group showed significantly higher laser doppler blood flow in the ischemic limb at days 7 and 14 after HLI. Increased microvascular density [percent area of CD31(+) cells] and reduced interstitial fibrosis in the ischemic limb muscle were also observed in the Muse group. mCherry-expressing Muse cells were found in the ischemic border zone and expressed CD31 but did not in the non-ischemic limb. Muse cells produced higher amounts of vascular endothelial growth factor (VEGF) than non-Muse cells under normoxic and hypoxic conditions in vitro. In the ischemic muscle, tissue VEGF concentration and angiogenesis-related genes such as Vegfa, Angpt1, Pdgfb, and Igf1 were significantly higher in the Muse group than in the other two groups. In addition, the proportion of M2 macrophages to total macrophages and the ratio of anti-inflammatory-related genes such as IL-10, Arg1, and CD206 per iNOS were significantly higher in the Muse group than in the other two groups. In summary, Muse cells exert pleiotropic effects in a mouse model of HLI, and therefore may provide a novel therapeutic approach for the treatment of PAD patients with severe limb ischemia.

Keywords: Muse cell; cell therapy; hindlimb ischemia; mesenchymal stem cell; peripheral arterial disease.