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Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue\u2010derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI\/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI\/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss\u2010of\u2010function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin\u2010treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac\u2010specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin\u2010treated ADSCs in mice subjected to MI\/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide\u2010induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1\/2\u2010SOD2, and ERK1\/2\u2010ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin\u2010treated ADSCs, respectively. Integrin <jats:italic>\u03b1<\/jats:italic>V\/<jats:italic>\u03b2<\/jats:italic>5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury.<\/jats:p>","DOI":"10.1002\/advs.202103697","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T10:30:23Z","timestamp":1642415423000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1933-8733","authenticated-orcid":false,"given":"Wenjun","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Cardiology Xijing Hospital Fourth Military Medical University  Xi'an 710032 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