A humanized engineered heart tissue platform for cardiotoxicity assessment.
Yao-Hui Sun, Daphne A Diloretto, Hillary K J Kao, Padmini Sirish, Christophe Morisseau, Rasheed Sule, Ming-Fo Hsu, Regan L Smithers, James Overton, Valeriy Timofeyev, Alexander Merleev, Gabriela Grigorean, Brett S Phinney, Emanual M Maverakis, Aldrin V Gomes, Fawaz G Haj, Jan A Nolta, James W Chan, Bruce D Hammock, Deborah K Lieu, Nipavan Chiamvimonvat
Abstract
Cardiovascular diseases (CVDs), many of which are influenced by exposure to environmental xenobiotics, lack physiologically relevant in vitro models for cardiotoxicity assessment. Although some pollutants have established associations with CVD, the effects of a wide range of potential toxicants remains unknown. Here, we developed a three-dimensional recellularized humanized engineered heart tissue (rHHT) platform by integrating decellularized human left ventricular extracellular matrix with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), yielding spontaneously contracting tissues that recapitulate key features of native ventricular myocardium. We also generated a hiPSC line stably expressing the calcium indicator GCaMP6f, enabling real-time and longitudinal monitoring of calcium transients. Using ethanol and rotenone as examples, we demonstrate that the rHHT platform provides a sensitive system for evaluating cardiotoxicity and is more stringent than conventional monolayer approaches. This study presents a scalable platform for xenobiotic cardiotoxicity assessment, with potential applicability to high-throughput screening, mechanistic studies, and future personalized medicine applications.