Understanding how heart muscle cells stop dividing and acquire the characteristics needed to sustain lifelong cardiac function remains one of the greatest challenges in cardiovascular biology. Leveraging human induced pluripotent stem (iPS) cell technology, a team led by Associate Professor Yoshinori Yoshida (Department of Clinical Application, CiRA, Kyoto University) and Associate Professor Antonio Lucena-Cacace (WPI-PRIMe, The University of Osaka) has identified PRDM16 as an important regulator governing the balance between proliferation and maturation in human iPSC-derived cardiomyocytes.

The study reveals that PRDM16 acts as a developmental "rheostat": low levels permit cardiomyocytes to retain proliferative competence, whereas higher levels facilitate the acquisition of structural, metabolic, and functional characteristics associated with more mature heart cells. The findings provide a framework for improving regenerative strategies and generating higher-quality cardiac tissues for disease modeling and drug discovery.

Successful cardiac regeneration requires overcoming a fundamental biological dilemma. During embryonic development, cardiomyocytes proliferate extensively to build the heart. Shortly after birth, however, these cells progressively withdraw from the cell cycle and adopt specialized functions that support lifelong contraction. While this maturation process is essential for cardiac performance, it severely restricts the regenerative capacity of the adult human heart following injury.

Similarly, cardiomyocytes generated from iPS cells remain relatively immature, limiting their utility for translational applications. Understanding the molecular signals coordinating the transition from proliferation to maturation has therefore become a major objective in regenerative medicine.

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," explains 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."

Indeed, PRDM16-deficient cardiomyocytes displayed elevated expression of proliferative regulators, including CDK1 and phospho-AKT, increased cell-cycle activity, and impaired acquisition of mature sarcomeric organization and mitochondrial function. Engineered heart tissues generated from these cells also exhibited diminished contractile performance.

Conversely, moderate overexpression of PRDM16 suppressed proliferation while promoting hallmarks of cardiomyocyte maturation, including cellular hypertrophy, increased expression of adult cardiac proteins such as TNNI3, enhanced oxidative metabolism, and reduced spontaneous beating frequency.

"Our findings suggest that PRDM16 functions as a molecular checkpoint guiding cardiomyocytes toward functional competence," says Yoshinori Yoshida, who supervised the study. "Understanding how this balance is achieved may ultimately allow us to generate cardiac tissues that are both physiologically relevant and clinically useful."

The study also raises the possibility that temporal manipulation of PRDM16 could one day contribute to regenerative strategies.

"One of the long-standing goals in cardiac biology has been to recover proliferative potential without permanently compromising maturation," notes Antonio Lucena-Cacace, co-corresponding author of the study. "PRDM16 appears to occupy an interesting position within this continuum. While mature cardiomyocytes require sufficient PRDM16 activity to acquire specialized functions, transient modulation of this pathway may provide opportunities to enhance regenerative responses or improve the quality of stem cell-derived cardiac models."

The researchers emphasize that further studies will be required to identify the direct genomic targets of PRDM16 and determine how its regulatory activity changes throughout cardiac development. Nevertheless, the present findings establish PRDM16 as a previously underappreciated determinant of human cardiomyocyte biology.

Published in Stem Cell Reports, this work places PRDM16 among a growing number of developmental regulators being explored to optimize iPS cell-derived cardiac systems. By clarifying how human cardiomyocytes transit between proliferation and maturation, the study advances efforts to engineer more faithful models of the human heart and develop future regenerative therapies.

Graphical abstract

• doi: 10.1016/j.stemcr.2026.103005