Abstract
Cardiac diseases are the leading cause of deaths worldwide; however, to date, there has been limited progress in the development of therapeutic options for these conditions. Animal models have been the most extensively studied methods to recapitulate a wide variety of cardiac diseases, but these models exhibit species-specific differences in physiology, metabolism and genetics, which lead to inaccurate and unpredictable drug safety and efficacy results, resulting in drug attrition. The development of human pluripotent stem cell (hPSC) technology in theory guarantees an unlimited source of human cardiac cells. These hPSC-derived cells are not only well suited for traditional two-dimensional (2-D) monoculture, but also applicable to more complex systems, such as three-dimensional (3-D) organoids, tissue engineering and heart on-a-chip. In this review, we discuss the application of hPSCs in heart disease modeling, cell therapy, and next-generation drug discovery. While the hPSC-related technologies still require optimization, their advances hold promise for revolutionizing cell-based therapies and drug discovery.
Highlights
Cardiac diseases, such as myocardial infarction and heart failure, have been the leading cause of deaths worldwide, few drugs are being approved yearly compared with many other disease area, resulting in a huge gap between clinical need and drug development (Fordyce et al, 2015)
The extrapolation of translatable data from animals data to guide the treatment of human heart disease has been difficult due to considerable species differences (Matsa et al, 2014). human pluripotent stem cell (hPSC) can potentially bridge this transitional gap by providing an unlimited source of human cardiac cells for biomedical research and drug discovery (Matsa et al, 2014)
Protocols that enable the generation of cardiomyocyte subtypes such as ventricular, atrial, and sinoatrial pacemaker cells, as well as non-myocyte cell types including endothelial cells and fibroblasts have been developed (Mummery et al, 2012; Weng et al, 2014; Lee et al, 2017; Protze et al, 2017; Williams and Wu, 2019; Zhang et al, 2019)
Summary
Cardiac diseases, such as myocardial infarction and heart failure, have been the leading cause of deaths worldwide, few drugs are being approved yearly compared with many other disease area, resulting in a huge gap between clinical need and drug development (Fordyce et al, 2015). Protocols that enable the generation of cardiomyocyte subtypes such as ventricular, atrial, and sinoatrial pacemaker cells, as well as non-myocyte cell types including endothelial cells and fibroblasts have been developed (Mummery et al, 2012; Weng et al, 2014; Lee et al, 2017; Protze et al, 2017; Williams and Wu, 2019; Zhang et al, 2019). These highly enriched populations of specific cardiomyocyte subtypes facilitate disease modeling and drug testing by recognizing cellular, molecular and functional heterogeneity within the heart. We highlight the application of available hPSC platforms for the pharmacologic evaluation and cardiac safety assessment of drugs (Figure 1)
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