Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes

The vast potential of human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) in preclin-ical models of cardiac pathologies, precision medicine, and drug screening remains to be fully realized because hiPSC-CMs are immature without adult-like characteristics. Here, we present a method to accel-erate hiPSC-CM maturation on a substrate, cardiac mimetic matrix (CMM), mimicking adult human heart ma-trix ligand chemistry, rigidity, and submicron ultrastructure, which synergistically mature hiPSC-CMs rapidly within 30 days. hiPSC-CMs matured on CMM exhibit systemic transcriptomic maturation toward an adult heart state, are aligned with high strain energy, metabolically rely on oxidative phosphorylation and fatty acid oxidation, and display enhanced redox handling capability, efficient calcium handling, and electrophys-iological features of ventricular myocytes. Endothelin-1-induced pathological hypertrophy is mitigated on CMM, highlighting the role of a native cardiac microenvironment in withstanding hypertrophy progression. CMM is a convenient model for accelerated development of ventricular myocytes manifesting highly special-ized cardiac-specific functions.

Automated summary

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have great potential in clinical models of cardiac pathologies, precision medicine, and drug screening. This study presents a method to accelerate the maturation of hiPSC-CMs on a cardiac mimetic matrix (CMM), resulting in rapid maturation within 30 days and exhibiting adult heart characteristics.