Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy
There is tremendous enthusiasm in the application of pluripotent stem cell (PSC) technology to cardiovascular medicine. PSCs can be expanded and subsequently induced to differentiate into cardiomyocytes (CMs) in vitro through various protocols. Because adult cardiomyocytes are non-proliferative and difficult to obtain from human patients, PSC-derived CMs serve as the most viable approach to generating large quantities of CMs ex vivo. However, the inability of conventional culture techniques to produce fully mature PSC-CMs remains a major hurdle to successful experimental and clinical use of these cells. In vivo, cardiomyocytes undergo numerous adaptive structural and functional changes during maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. To date, the specific mechanisms regulating CM maturation remain unknown, impeding further clinical/research use of PSC-CMs.
We are interested in understanding the molecular mechanisms underlying maturation in vivo, and how these pathways are dysregulated in PSC-CMs. Through transcriptomic analysis, we found that while PSC-CMs are arrested at a mid-embryonic maturation state (left), they have numerous aberrant gene regulatory networks (right). Interestingly, when PSC-CMs are transplanted into a neonatal heart, they achieve full maturation status. These results suggest that the neonatal environment uniquely regulates coordinated maturation of CMs, which is lost during in vitro culture.