{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T03:40:07Z","timestamp":1793504407459,"version":"4.5.0"},"reference-count":236,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brown University 2023 OVPR Seed Award","id":[{"id":"https:\/\/ror.org\/05gq02987","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Health R01 HL173938"},{"name":"Brown University School of Engineering Carl Nielsen","id":[{"id":"https:\/\/ror.org\/05gq02987","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NSF-GRFP and AAUW"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Myocardial infarction (MI) is a severe hypoxic event, resulting in the loss of up to one billion cardiomyocytes (CMs). Due to the limited intrinsic regenerative capacity of the heart, cell-based regenerative therapies, which feature the implantation of stem cell-derived cardiomyocytes (SC-CMs) into the infarcted myocardium, are being developed with the goal of restoring lost muscle mass, re-engineering cardiac contractility, and preventing the progression of MI into heart failure (HF). However, such cell-based therapies are challenged by their susceptibility to oxidative stress in the ischemic environment of the infarcted heart. To maximize the therapeutic benefits of cell-based approaches, a better understanding of the heart environment at the cellular, tissue, and organ level throughout MI is imperative. This review provides a comprehensive summary of the cardiac pathophysiology occurring during and after MI, as well as how these changes define the cardiac environment to which cell-based cardiac regenerative therapies are delivered. This understanding is then leveraged to frame how cell culture treatments may be employed to enhance SC-CMs\u2019 hypoxia resistance. In this way, we synthesize both the complex experience of SC-CMs upon implantation and the engineering techniques that can be utilized to develop robust SC-CMs for the clinical translation of cell-based cardiac therapies.<\/jats:p>","DOI":"10.3390\/bioengineering12020154","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T04:47:31Z","timestamp":1738817251000},"page":"154","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-5267","authenticated-orcid":false,"given":"Kiera D.","family":"Dwyer","sequence":"first","affiliation":[{"name":"Institute for Biology, Engineering, and Medicine, School of Engineering, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1821-3375","authenticated-orcid":false,"given":"Caroline A.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Institute for Biology, Engineering, and Medicine, School of Engineering, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareen L. K.","family":"Coulombe","sequence":"additional","affiliation":[{"name":"Institute for Biology, Engineering, and Medicine, School of Engineering, Brown University, Providence, RI 02912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0945-053X(03)00006-4","article-title":"Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis","volume":"22","author":"Myllyharju","year":"2003","journal-title":"Matrix Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20712","DOI":"10.1074\/jbc.R115.662627","article-title":"Protein hydroxylation catalyzed by 2-oxoglutarate-dependent oxygenases","volume":"290","author":"Markolovic","year":"2015","journal-title":"J. Biol. 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