Human iPSC-derived cardiac-specific extracellular matrix scaffolds for cardiomyocyte maturation and post-myocardial infarction repair

Myocardial infarction (MI) remains a leading cause of heart failure due to the limited regenerative capacity of the adult myocardium. The therapeutic efficacy of current engineered cardiac patches is hindered by their simplistic scaffold composition and lack of structural organization. This study presents a bioactive, anisotropic extracellular matrix (ECM) scaffold derived from human induced pluripotent stem cell-differentiated cardiac fibroblasts (hiPSC-CF-ECM) that combines cardiac-specific proteins and growth factors with complex structural composition. Compared to primary cardiac fibroblast ECM (pri-CF-ECM) and human dermal fibroblast ECM (hDF-ECM), hiPSC-derived cardiomyocytes (hiPSC-CMs) cultured on the cardiac-specific ECM scaffold exhibited enhanced maturation, as confirmed by bulk RNA sequencing, electrophysiological mapping, and optical-based strain analysis. In an immune-competent rat MI model, the hiPSC-CF-ECM transplantation preserved cardiac function, increased ejection fraction, and reduced maladaptive remodeling. These findings highlight hiPSC-CF-ECM as a promising biomimetic scaffold for cardiac tissue engineering and MI treatment.