The long and winding road of cardiomyocyte maturation

Knowledge about the molecular mechanisms regulating cardiomyocyte (CM) proliferation and differentiation has increased exponentially in recent years. Such insights together with the availability of more efficient protocols for generation of CMs from induced pluripotent stem cells (iPSCs) have raised expectations for new therapeutic strategies to treat congenital and non-congenital heart diseases. However, the poor regenerative potential of the postnatal heart and the incomplete maturation of iPSC-derived CMs represent important bottlenecks for such therapies in future years. CMs undergo dramatic changes at the doorstep between prenatal and postnatal life, including terminal cell cycle withdrawal, change in metabolism, and further specialization of the cellular machinery required for high-performance contraction. Here, we review recent insights into pre- and early postnatal developmental processes that regulate CM maturation, laying specific focus on genetic and metabolic pathways that control transition of CMs from the embryonic and perinatal to the fully mature adult CM state. We recapitulate the intrinsic features of CM maturation and highlight the importance of external factors, such as energy substrate availability and endocrine regulation in shaping postnatal CM development. We also address recent approaches to enhance maturation of iPSC-derived CMs in vitro, and summarize new discoveries that might provide useful tools for translational research on repair of the injured human heart.