Human heart disease: lessons from human pluripotent stem cell-derived cardiomyocytes

Abstract

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.

Keywords: Cardiac arrhythmia; Cardiac disease; Cardiomyopathy; Cardiovascular disease; Disease modeling; Drug screening; Human pluripotent stem cell-derived cardiomyocytes; Safety pharmacology.

Fig. 1

Schematic representation of cardiomyocyte structure and relevant cellular and molecular components that are mutated in cardiac diseases. This schematic shows the cardiac proteins encoded by mutated genes for which hiPSCs have been generated and reviewed here. Disease genes of interest, which are also listed in Table 3, are located in different compartments of the cardiomyocyte, such as the extracellular matrix, sarcoplasmic reticulum (SR), cytoskeleton, sarcomere, desmosome, lysosome, mitochondrion, and the nucleus