TY - JOUR
T1 - Intravenous administration of human Muse cells recovers blood flow in a mouse model of hindlimb ischemia
AU - Hori, Yusuke
AU - Kitani, Tomoya
AU - Yanishi, Kenji
AU - Suga, Takaomi
AU - Kogure, Masaya
AU - Kusaba, Tetsuro
AU - Kushida, Yoshihiro
AU - Dezawa, Mari
AU - Matoba, Satoaki
N1 - Funding Information:
This work was supported by a joint research grant from Life Science Institute, Inc., (to TKu and SM) and SENSHIN Medical Research Foundation (to TKi), a Grant-in-Aid for Scientific Research (20H04510), and a Grant-in-Aid for Exploratory Research (19H22648), Japan Society for the Promotion of Science. Life Science Institute, Inc. was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.
Publisher Copyright:
Copyright © 2022 Hori, Kitani, Yanishi, Suga, Kogure, Kusaba, Kushida, Dezawa and Matoba.
PY - 2022/11/11
Y1 - 2022/11/11
N2 - 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.
AB - 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.
KW - Muse cell
KW - cell therapy
KW - hindlimb ischemia
KW - mesenchymal stem cell
KW - peripheral arterial disease
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U2 - 10.3389/fcvm.2022.981088
DO - 10.3389/fcvm.2022.981088
M3 - Article
AN - SCOPUS:85148355401
SN - 2297-055X
VL - 9
JO - Frontiers in Cardiovascular Medicine
JF - Frontiers in Cardiovascular Medicine
M1 - 981088
ER -