A research team led by Associate Professor Yoshinori Yoshida of Kyoto University and Associate Professor Antonio Lucena-Cacace of The University of Osaka announced on Aug. 7 that they have identified PRDM16 as an important regulator balancing proliferation and maturation in human induced pluripotent stem cell-derived cardiomyocytes.
The study shows that PRDM16 acts as a developmental rheostat, with low levels allowing cardiomyocytes to retain the ability to proliferate, while higher levels facilitate the acquisition of structural, metabolic, and functional characteristics associated with mature heart cells. The researchers said these findings provide a framework for improving regenerative strategies and generating higher-quality cardiac tissues for disease modeling and drug discovery.
During embryonic development, cardiomyocytes proliferate extensively to build the heart. After birth, these cells withdraw from the cell cycle and adopt specialized functions needed for lifelong contraction. While this maturation is essential for cardiac performance, it restricts the adult human heart's regenerative capacity following injury. Similarly, cardiomyocytes generated from iPS cells remain relatively immature, limiting their utility for translational applications.
Using fluorescent cell-cycle reporter systems, transcriptomic analyses, engineered heart tissues, and gain- and loss-of-function approaches, the team demonstrated that PRDM16 occupies a central position in this developmental transition. "When we reduced PRDM16 levels, cardiomyocytes regained aspects of proliferative competence that are normally lost during maturation," said Kanae Tani, researcher and first author of the study. "At the same time, these cells struggled to acquire adult-like characteristics, suggesting that PRDM16 is involved in coordinating the trade-off between growth and specialization."
The researchers found that PRDM16-deficient cardiomyocytes showed increased expression of proliferative regulators such as CDK1 and phospho-AKT but had impaired acquisition of mature sarcomeric organization and mitochondrial function; engineered heart tissues from these cells also exhibited diminished contractile performance. Conversely, moderate overexpression of PRDM16 suppressed proliferation while promoting features associated with maturation, including cellular hypertrophy and enhanced oxidative metabolism.
"Our findings suggest that PRDM16 functions as a molecular checkpoint guiding cardiomyocytes toward functional competence," said Yoshida. The team stated further studies will be required to identify direct genomic targets of PRDM16 and determine how its regulatory activity changes throughout cardiac development.
