Engineering the Cellular Microenvironment for Human Induced Pluripotent Stem Cell Cardiac Differentiation: Beyond Wnt Signaling

Abstract

Human induced pluripotent stem cells (hiPSCs) have revolutionized cardiovascular research by providing a renewable source of patient-specific cardiomyocytes for disease modeling, drug discovery, precision medicine, and regenerative therapies. Temporal modulation of canonical Wnt/β-catenin signaling has established the current gold standard for efficient and reproducible cardiac differentiation under chemically defined conditions. However, conventional Wnt-based protocols consistently generate cardiomyocytes with fetal-like structural, electrophysiological, metabolic, and contractile characteristics, highlighting that lineage specification alone is insufficient to achieve functional maturation. This review discusses recent advances in engineering the cardiac developmental niche by integrating extracellular matrix remodeling, biomaterials, biomechanical and bioelectrical stimulation, metabolic regulation, multicellular interactions, and microfluidic technologies to better recapitulate the dynamic microenvironment of human cardiogenesis. We further examine how emerging bioengineered platforms, including engineered heart tissues, cardiac organoids, and heart-on-chip systems, enhance the physiological relevance of hiPSC-derived cardiac models. Finally, we discuss future perspectives arising from the convergence of developmental biology, tissue engineering, biomaterials, artificial intelligence, and microphysiological systems, proposing that the next generation of cardiac differentiation platforms will depend on integrating canonical Wnt signaling within biomimetic developmental microenvironments to generate mature human cardiac tissues with enhanced translational potential. By advancing physiologically relevant human cardiac models for disease modeling, drug discovery, and regenerative medicine, this work also supports the research and innovation priorities underlying Sustainable Development Goal 3 (SDG 3), particularly those related to reducing the burden of non-communicable diseases and strengthening health-related research and development.