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Cell-based therapies using endothelial cells (ECs) have shown promise in promoting angiogenesis for PAD, but challenges remain in obtaining sufficient ECs from human tissues. Induced pluripotent stem cells (iPSCs) provide a potential solution, though immune rejection issues arise due to human leukocyte antigen (HLA) mismatches. The depletion of HLA class I and II through gene editing aims to broadly avoid lymphocyte recognition\u00a0and can be achieved by inactivating\u00a0\u03b22-microglobulin (B2M)\u00a0and class II transactivator (CIITA). However, B2M inactivation can lead to a \u2018missing self\u2019 killing response\u00a0by NK cells and macrophages. To overcome this, we proposed universal iPSCs by knocking out B2M and CIITA and over-expressing CD24 to reduce immune rejection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Universal iPSCs were tested for their pluripotency and ability to differentiate into ECs. The stimulation of universal iPSC-derived endothelial cells (U-ECs) to T and NK cells was evaluated by activation marker using flow cytometry. We generated a humanized mouse model by intravenously injecting CD34\n                      <jats:sup>+<\/jats:sup>\n                      \u00a0hematopoietic stem cells isolated from umbilical cord blood into NSG mice. Finally, we induced a humanized PAD mouse model by removing the femoral artery of the left hindlimb. Then we injected U-ECs, demonstrating the therapeutic efficacy of U-ECs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We generated hypoimmunogenic universal iPSC by knocking out B2M and CIITA, along with over-expressing CD24, and confirmed that their pluripotency was maintained. We demonstrated that U-ECs exhibit functional endothelial properties and reduced immunogenicity, effectively mitigating immune recognition from both adaptive and innate immune responses. U-ECs survived in significantly greater numbers after transplantation and elicited a weaker immune response in humanized mice. Then we induced hindlimb ischemia in humanized mice to establish a humanized PAD model. U-ECs induced effective angiogenic capabilities, leading to significant blood flow restoration in ischemic limbs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrates the feasibility of creating hypoimmunogenic iPSCs and their derivatives that can reduce immune response and function effectively in vivo.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-025-04554-5","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T18:19:08Z","timestamp":1754504348000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Therapeutic effects of hypoimmunogenic universal human iPSC-derived endothelial cells in a humanized mouse model of peripheral artery disease"],"prefix":"10.1186","volume":"16","author":[{"given":"Jungju","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam Gyo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dasom","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Ji","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeong-Cheol","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daekee","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Hyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9322-741X","authenticated-orcid":false,"given":"Kyung-Sun","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"issue":"9901","key":"4554_CR1","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1016\/S0140-6736(13)61249-0","volume":"382","author":"FGR Fowkes","year":"2013","unstructured":"Fowkes FGR, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. 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J Vasc Surg. 2005;41(2):312\u201320. https:\/\/doi.org\/10.1016\/j.jvs.2004.11.012.","journal-title":"J Vasc Surg"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-025-04554-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-025-04554-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-025-04554-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T22:10:17Z","timestamp":1757369417000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-025-04554-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4554"],"URL":"https:\/\/doi.org\/10.1186\/s13287-025-04554-5","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,6]]},"assertion":[{"value":"24 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved under the project title of \u201cDevelopment of immune-modulated 3D tissue complex and regeneration technology for the incurable liver disease\u201d by the Seoul National University Institutional Review Board (IRB No. 2212\/001\u2013014, 29th December 2022). The human iPSC was manufactured with hDF purchased from the site below (\n                      \n                      ) and obtained from the MARU THERAPEUTICS under the project title of \u201cDevelopment of anti-cancer immune cell therapy and antiviral cell therapy derived from human-induced pluripotent stem cells\u201d (IRB NO. P01-202110\u201331-009, 20th October 2021) as described in our previous study [\n                      \n                      ]. Human umbilical cord blood was provided by the Seoul Metropolitan Government Public Cord Blood Bank (Allcord, Korea) under the project title of \u201cDevelopment of immune-modulated 3D tissue complex and regeneration technology for the incurable liver disease\u201d by the Seoul National University Institutional Review Board (IRB No. E2307\/001\u2013006, 4th July 2023). Written informed consent was obtained from the parents or legal guardians of all donors for the collection and use of cord blood samples. All experimental procedures were performed in accordance with National Institutes of Health institutional guidelines and were approved under the project title of \u201cProduction of humanized mouse for establishing stem cells from which immunogenic genes have been removed\u201d by the University Administrative Panel on Laboratory Animal Care (IACUC SNU-230621\u20134-2, 12th July 2024) and by the Seoul National University Hospital Biomedical Research Institute (IACUC 24\u20130036-S1A0, 29th February 2024).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"430"}}