Cyclin A2 induces cytokinesis in human adult cardiomyocytes and drives reprogramming in mice

Cyclin A2 (CCNA2), a master cell cycle regulator silenced in postnatal cardiomyocytes, promotes cardiac repair in animal models. However, its effect on cytokinesis in adult human cardiomyocytes was previously unknown. We engineered a replication-deficient adenoviral vector encoding human CCNA2 under the cardiac Troponin T promoter and delivered it to freshly isolated cardiomyocytes from adult human hearts. Time-lapse live imaging revealed the induction of complete cytokinesis with preservation of sarcomeres and calcium mobilization in redifferentiated daughter cardiomyocytes. Single-nucleus transcriptomic profiling of CCNA2-transgenic and non-transgenic mouse hearts uncovered a cardiomyocyte subpopulation characterized by enrichment of cytokinesis, proliferation, and reprogramming gene signatures. Ultra-deep bulk RNA sequencing of adult and fetal human hearts further highlighted reprogramming pathways relevant to CCNA2-induced effects. Together, these findings demonstrate that CCNA2 can reinitiate cytokinesis in adult human cardiomyocytes, illuminating conserved molecular programs that support its promise as a regenerative gene therapy for the heart.