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 remains 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 induction of complete cytokinesis with preservation of sarcomeres and calcium mobilization in redifferentiated daughter cardiomyocytes. To uncover underlying transcriptional mechanisms, single-nucleus transcriptomics of CCNA2-transgenic versus non-transgenic mouse hearts identified a cardiomyocyte subpopulation enriched for cytokinesis, proliferative, and reprogramming genes. 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 and illuminate conserved molecular programs, supporting its promise as a regenerative gene therapy for the heart. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/583057v7_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@b9cfa9org.highwire.dtl.DTLVardef@f0720eorg.highwire.dtl.DTLVardef@1d020b2org.highwire.dtl.DTLVardef@112c28b_HPS_FORMAT_FIGEXP M_FIG C_FIG CCNA2 Induces Cytokinesis and Drives Proliferation and Reprogramming of Adult Cardiomyocytes: An Integrative Transcriptomic Analysis across Human and Mouse Models.