{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:17:58Z","timestamp":1790644678966,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T00:00:00Z","timestamp":1617321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL-128406"],"award-info":[{"award-number":["R01-HL-128406"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL-150352"],"award-info":[{"award-number":["R01-HL-150352"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p &lt; 0.05; Faber score, p &lt; 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p &lt; 0.0001), increased fiber area (p &lt; 0.0001), and enhanced capillary density (p &lt; 0.01); microCT showed more arterioles (&lt;96 \u03bcm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p &lt; 0.05) and increased numbers of M2-type macrophages (p &lt; 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p &lt; 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p &lt; 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.<\/jats:p>","DOI":"10.3390\/cells10040792","type":"journal-article","created":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T10:34:09Z","timestamp":1617359649000},"page":"792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-9309","authenticated-orcid":false,"given":"Xixiang","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University and Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China"},{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Gao","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Vascular Ultrasound, Xuanwu Hospital, Capital Medical University, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanta","family":"Gorecka","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7307-8664","authenticated-orcid":false,"given":"John","family":"Langford","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiesi","family":"Luo","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA"},{"name":"Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA"},{"name":"Department of Pathology, Yale University, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9187-8403","authenticated-orcid":false,"given":"Yutaka","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery and Sciences, Kyushu University, Fukuoka 812-8582, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianrui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University and Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongquan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University and Institute of Vascular Surgery, Capital Medical University, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Qyang","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA"},{"name":"Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA"},{"name":"Department of Pathology, Yale University, New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5022-7367","authenticated-orcid":false,"given":"Alan","family":"Dardik","sequence":"additional","affiliation":[{"name":"Vascular Biology &amp; Therapeutics Program, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA"},{"name":"Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, USA"},{"name":"Department of Surgery, VA Connecticut Healthcare System, West Haven, CT 06516, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.amepre.2006.12.010","article-title":"Ethnic-Specific Prevalence of Peripheral Arterial Disease in the United States","volume":"32","author":"Allison","year":"2007","journal-title":"Am. 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