Maturation of human cardiac organoids enables complex disease modeling and drug discovery
Mark Pocock, Janice D. Reid, Harley Robinson, Natalie Charitakis, James R. Krycer, Simon R. Foster, Rebecca L. Fitzsimmons, Mary Lor, Lynn Devilée, Christopher Batho, Natasha Tuano, Sara E. Howden, Katerina Vlahos, Kevin I. Watt, Adam T. Piers, Kaitlyn Bibby, James W. McNamara, Rebecca Sutton, Valerii Iaprintsev, Jacob Mathew, Holly K. Voges, Patrick R.J. Fortuna, Sebastian Bass-Stringer, Céline Vivien, James Rae, Robert G. Parton, Anthony B. Firulli, Leszek Lisowski, Hannah Huckstep, Sean J. Humphrey, Sean Lal, Igor E. Konstantinov, Robert G Weintraub, David A. Elliott, Mirana Ramialison, Enzo R. Porrello, Richard J. Mills, James E. Hudson
Abstract
Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5' AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening.