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Subsequent advances in directed differentiation made the generation of human iPSC-derived cardiac myocytes reliable and scalable. Despite this progress, a central limitation has remained: these cells are developmentally immature, resembling fetal cardiac myocytes in structure, metabolism, and function. This immaturity restricts their utility for modeling adult-onset disease, predicting drug responses, and achieving clinical translation. Maturation is now understood as a multifactorial symphony, requiring coordinated molecular, structural, and environmental inputs rather than single interventions. As a result, the field is shifting toward integrative approaches that incorporate 3D architecture, multicellular systems, and biomimetic environments to better replicate native cardiac tissue. While fully adult-like myocardium remains an ongoing goal, advances in bioengineering and system-level design are narrowing the gap, with success increasingly defined by the generation of functional cardiac tissue rather than isolated cell maturity.<\/jats:p>","DOI":"10.3390\/cells15111019","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"1019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering Human Myocardium: Integrating the Maturation of hiPSC-Derived Cardiac Myocytes Across Genetic, Structural, Physiological and Multicellular Systems"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-1329","authenticated-orcid":false,"given":"Nora","family":"Hosny","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"},{"name":"Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houda","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7694-0907","authenticated-orcid":false,"given":"John","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Schreifels","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3882-4326","authenticated-orcid":false,"given":"Joseph M.","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101622","DOI":"10.1016\/j.cpcardiol.2023.101622","article-title":"Global Cardiovascular Diseases Death Rate Prediction","volume":"48","author":"Gaidai","year":"2023","journal-title":"Curr. 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