Delivery of Cyclin A2 (CCNA2) induced complete cytokinesis in adult human cardiomyocytes and drove reprogramming gene signatures in mouse models, supporting its potential as a regenerative gene therapy.
Does Cyclin A2 (CCNA2) gene delivery induce cytokinesis and reprogramming in adult human cardiomyocytes and mouse models?
CCNA2 gene therapy can reinitiate cytokinesis in adult human cardiomyocytes, highlighting its potential as a regenerative therapy for the heart.
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.
Bouhamida et al. (Mon,) conducted a other in Cardiac regeneration. Adenoviral vector encoding human CCNA2 vs. Non-transgenic controls was evaluated on Induction of cytokinesis and transcriptomic reprogramming. Delivery of Cyclin A2 (CCNA2) induced complete cytokinesis in adult human cardiomyocytes and drove reprogramming gene signatures in mouse models, supporting its potential as a regenerative gene therapy.