PRDM16 Modulates Aspects of Cell-Cycle Dynamics and Maturation in Human iPSC-Derived Cardiomyocytes

Understanding the molecular mechanisms that mediate entry into quiescent states of cardiac tissues, along with their associated metabolic rewiring, is crucial for comprehending the postnatal changes driving physiological hypertrophy and functional maturation. PRDM16 has been identified as a critical regulator of both proliferation and maturation in fetal-like human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our study demonstrates that PRDM16 orchestrates the proliferative axis of hiPSC-CMs by modulating CDK1 and phospho-AKT levels, two key drivers of cardiac proliferation. Reduced PRDM16 expression significantly impairs the metabolic and structural maturation of hiPSC-CMs, leading to dysregulated sarcomeric protein expression ratios and compromised engineered heart tissue (EHT) function. Conversely, mild PRDM16 overexpression promotes metabolic shifts and structural protein changes toward maturation. These findings provide new insights into the molecular mechanisms governing cardiomyocyte development and highlight PRDM16 as a potential therapeutic target for enhancing cardiac regeneration and repair, since transient PRDM16 downregulation creates a roadblock to maturation in favor of proliferation. Overall, this work underscores the central role of PRDM16 in controlling the proliferation-maturation axis of cardiomyocyte biology.