Center for iPS Cell Research and Application (CiRA), Kyoto University Kyoto, Kyoto, Japan
Abstract: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold significant potential for clinical applications, including disease modeling, regenerative therapy, and drug screening. However, they lag behind in acquiring the structural, physiological, and metabolic phenotypes characteristic of functional maturity. This immaturity presents a major obstacle to their full utility in clinical settings. Whereas adult cardiomyocytes are generally postmitotically arrested in the G0 (quiescent) phase, hiPSC-CMs retain residual proliferative activity. Chemical inhibition of mTOR signaling is known to enhance hiPSC-CM maturity through p53-induced quiescence. However, p53 is not the sole factor mediating complete cell cycle withdrawal in cardiac cells, as proliferative signaling, such as phosphorylated AKT, remains active. Among the genes implicated in promoting cardiac quiescence postnatally, we have identified PRDM16 as a key regulator of both proliferation and maturation. Increased PRDM16 expression is inversely correlated with proliferative states, suggesting that elevated PRDM16 levels promote maturation while restricting proliferation. In contrast, proliferative hiPSC-CMs exhibit low PRDM16 expression and reduced maturity, whereas decreased PRDM16 levels enhance cardiac proliferation and allow cells to bypass G0 entry. Ectopic downregulation of PRDM16 in hiPSC-CMs impedes maturation under both basal and mTOR-inhibited conditions. Conversely, preliminary data indicate that ectopic overexpression of PRDM16 enhances transcriptomic maturation. These findings highlight PRDM16’s dual role in balancing proliferation and maturation in cardiomyocytes, providing insights into cardiac developmental biology and potential avenues for regenerative therapies. Further exploration of PRDM16 modulation could lead to novel strategies for enhancing cardiac repair and function in disease contexts.
