Maturation of human pluripotent stem cell derived cardiomyocytes in vitro and in vivo

Human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) represent an inexhaustible cell source for in vitro disease modeling, drug discovery and toxicity screening, and potential therapeutic applications. However, currently available differentiation protocols yield populations of hPSC-CMs with an immature phenotype similar to cardiomyocytes in the early fetal heart. In this review, we consider the developmental processes and signaling cues involved in normal human cardiac maturation, as well as how these insights might be applied to the specific maturation of hPSC-CMs. We summarize the state-of-the-art and relative merits of reported hPSC-CM maturation strategies including prolonged duration in culture, metabolic manipulation, treatment with soluble or substrate-based cues, and tissue engineering approaches. Finally, we review the evidence that hPSC-CMs mature after implantation in injured hearts as such in vivo remodeling will likely affect the safety and efficacy of a potential hPSC-based cardiac therapy.