Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening

Abstract

Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

Figure 1

Potential applications of human induced pluripotent stem cell-derived cardiomyocytes towards cardiovascular medicine and therapy. Patient fibroblasts or blood cells are obtained and reprogrammed into human induced pluripotent stem cell (hiPSC) colonies by introduction of pluripotency factors - Oct4, Klf4, Sox2, and c-Myc. Subsequently, hiPSCs are differentiated directly into >95% cardiomyocytes using high efficiency protocols and non-cardiomyocyte depletion strategies. These purified hiPSC cardiomyocytes could then be utilized for autologous cell therapy, in vitro disease modeling, or high throughput drug screening studies. RBC, red blood cell.