MicroRNA-mediated maturation of human pluripotent stem cell-derived cardiomyocytes: Towards a better model for cardiotoxicity?

Human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) are a promising human cardiac model system for drug development and toxicity screening, along with cell therapy and mechanistic research. The scalable differentiation of human PSCs into CMs provides a renewable cell source that overcomes species differences present in rodent primary CMs. In addition, induced pluripotent stem cell (iPSC) technology allows for development of patient-specific CMs, representing a valuable tool that may lead to better prediction, prevention, and treatment of cardiovascular diseases in this new era of precision medicine. However, the utility of PSC-CMs as an in vitro model is currently limited by their immature phenotype when compared to adult CMs. Recent work has identified microRNAs (miRNAs) as critical regulators of heart development and function. These studies have shown that miRNAs are essential to key processes that span the life cycle of a cardiomyocyte, including proliferation, hypertrophy, beating rhythm, and apoptosis. Importantly, emerging evidence strongly suggests that modulation of select miRNAs can enhance the maturation of PSC-CMs. Here, we review key miRNAs associated with heart development and function, and discuss strategies to promote PSC-CM maturation, focusing on current knowledge surrounding miRNA-based approaches and the application of PSC-CMs with respect to drug screening and disease models. Ultimately, it is likely that combinations of both miRNA and non-miRNA maturation strategies may collectively provide the best path forward for producing mature cardiomyocytes in vitro.