Engineering Human Myocardium: Integrating the Maturation of hiPSC-Derived Cardiac Myocytes Across Genetic, Structural, Physiological and Multicellular Systems

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Abstract
The landscape of human cardiac biology was transformed by the discovery that adult somatic cells can be reprogrammed into induced pluripotent stem cells, enabling patient-specific disease modeling, drug testing, and regenerative strategies without the prior ethical or biological constraints. 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.
Funding Information
  • NIH (NIH R01AR079477)
  • NIH (NIH R01HL132874)
  • MDA
  • Gregory Marzolf Jr. Foundation
  • American Heart Association
  • University of Minnesota

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