Functional Properties of Engineered Heart Slices Incorporating Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Summary: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for cardiac studies, but their structural and functional immaturity precludes their use as faithful models of adult myocardium. Here we describe engineered heart slices (EHS), preparations of decellularized porcine myocardium repopulated with hiPSC-CMs that exhibit structural and functional improvements over standard culture. EHS exhibited multicellular, aligned bundles of elongated CMs with organized sarcomeres, positive inotropic responses to isoproterenol, anisotropic conduction of action potentials, and electrophysiological functionality for more than 200 days. We developed a new drug assay, GRIDS, that serves as a “fingerprint” of cardiac drug sensitivity for a range of pacing rates and drug concentrations. GRIDS maps characterized differences in drug sensitivity between EHS and monolayers more clearly than changes in action potential durations or conduction velocities. EHS represent a tissue-like model for long-term culture, structural, and functional improvement, and higher fidelity drug response of hiPSC-CMs. : While decellularized myocardium provides biological cues that direct cardiomyocytes organization and function, repopulating it to create a highly functional electrical and mechanical syncytium has proved challenging. Blazeski and colleagues have created engineered heart slices from thin decellularized sheets, and heart cells derived from reprogrammed human skin cells, that can be used for long-term electrophysiological and contractile studies and drug testing. Keywords: cardiac tissue engineering, extracellular matrix, electrophysiology, induced pluripotent stem cells, scaffold