{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:01:02Z","timestamp":1785402062544,"version":"3.56.0"},"posted":{"date-parts":[[2024,2,17]]},"group-title":"Pathology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T00:00:00Z","timestamp":1708128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["U02HL148690"],"award-info":[{"award-number":["U02HL148690"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Intramyocardial injection of human pluripotent stem cell-derived cardiomyocytes following a myocardial infarction (MI) improves cardiac function in large animal models, but associated ventricular arrhythmias are major safety concern. We hypothesized that transendocardial injection of human induced pluripotent stem cell (hiPSC)-derived committed cardiac progenitor cells (CCPs), combined with cardiac fibroblast-derived extracellular matrix (cECM) to enhance cell retention, will generate cardiac tissue grafts improving contractility without triggering ventricular arrhythmias.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>hiPSCs were differentiated using bioreactors and small molecules to produce committed cardiac progenitor cells (CCPs). MI was created using a coronary artery balloon occlusion and reperfusion model in Yucatan mini pigs. Four weeks later, epicardial needle injections of CCPs+cECM were performed in a small initial feasibility cohort (n=6), and then transendocardial injections of CCPs+cECM (n=14), CCPs alone (n=14), cECM alone (n=4) or vehicle control (n=13) into the peri-infarct region in a randomized cohort. Arrhythmias were evaluated using implanted event recorders. Magnetic resonance imaging (MRI) and invasive pressure-volume assessment were used to evaluate left ventricular anatomic and functional performance. Detailed histology was performed to detect and characterize human grafts.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A scalable biomanufacturing protocol was developed generating CCPs which can efficiently differentiate into cardiomyocytes or endothelial cells in vitro. Intramyocardial delivery of CCPs to post-MI porcine hearts resulted in engraftment and differentiation of CCPs to form ventricular cardiomyocyte rich grafts. There was no significant difference in cardiac MRI-based measured cardiac volumes or function between control, CCP and CCP+cECM groups; however, pressure-volume analysis showed an improvement in dobutamine-stimulated functional reserve in CCP and CCP+cECM groups. Delivery of CCPs did not result in tumors or ventricular arrhythmias.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Transendocardial delivery of CCPs with or without cECM into post-MI porcine hearts resulted in comparable human cardiomyocyte grafts which did not improve resting LV function but did improve stress-induced contractile reserve without triggering ventricular arrhythmias.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.02.14.580375","type":"posted-content","created":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T23:46:29Z","timestamp":1708213589000},"source":"Crossref","is-referenced-by-count":4,"title":["Human iPSC-derived Committed Cardiac Progenitors Generate Cardiac Tissue Grafts in a Swine Ischemic Cardiomyopathy Model without Triggering Ventricular Arrhythmias"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0761-6038","authenticated-orcid":false,"given":"Amish N.","family":"Raval","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin, Madison, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4366-4424","authenticated-orcid":false,"given":"Eric G.","family":"Schmuck","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav","family":"Leonov","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushmita","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Jae","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylee","family":"Wilker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Conklin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Wisconsin, Madison, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Hacker","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, 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