A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells. [Display omitted] •Positive force frequency and post-rest potentiation are achieved in human tissues•Engineered atrial and ventricular tissues have distinct electrophysiology and drug responses•Atrio-ventricular tissues show spatially confined drug responses•Long-term electrical conditioning enables polygenic cardiac disease modeling A scalable cardiac tissue cultivation platform enables assessment of multiple parameters of atrial and ventricular tissue function, drug testing, and disease modeling.