New cardiac research unveils unique adaptability of mononuclear polyploid cardiomyocytes, offering clues for heart regeneration studies

A newly published study in Protein & Cell identifies Chaf1a as a critical regulator that governs karyokinesis during early postnatal heart development, and reveals unexpected functional resilience of mononuclear polyploid (MNPP) cardiomyocytes that challenges established understanding of cardiac endowment mechanisms.

Led by researchers from Tongji University and collaborating institutions, the team constructed a Chaf1a conditional knockout mouse model, in which perinatal deletion of Chaf1a triggers replication-associated DNA damage response and arrests the cell cycle at the G2/M checkpoint. This intervention blocks normal karyokinesis in neonatal cardiomyocytes, generating a mature myocardium where 65.32% of cells are MNPP cardiomyocytes, compared to merely 4.05% in wild-type controls. Notably, the knockout heart has only half the total number of cardiomyocytes (severely reduced cardiac endowment), a scenario previously reported to cause neonatal lethality in models with binuclear cardiomyocyte dominance.

Against conventional expectations, the MNPP-dominant hearts maintained stable, non-pathological cardiac function for up to 6 months. The cardiomyocytes launched physiological compensatory hypertrophy to offset the reduced cell count, with no pathological hypertrophy markers or severe fibrosis detected at 3 months, and the mice performed equivalently to wild-type littermates in treadmill endurance tests. The research team confirmed that Chaf1a exerts this regulatory effect exclusively within the perinatal proliferative window, as inducing Chaf1a deletion in adult cardiomyocytes produced no detectable abnormalities in nuclearity or cardiac function.

This work provides a brand new in vivo model to dissect the distinct physiological roles of MNPP cardiomyocytes, and offers critical clues to explain why human hearts are naturally enriched with MNPP cardiomyocytes while rodent hearts are dominated by binuclear counterparts. The findings lay a foundational framework for future exploration of cardiac regeneration strategies targeting cardiomyocyte ploidy regulation, and open new directions for developing interventions to improve long-term cardiac functional reserve.