Cyclin A2 Induces Human Adult Cardiomyocyte Cytokinesis and Elicits Cardiomyocyte Reprogramming and Dedifferentiation

Area of Science:

• Cardiovascular Biology
• Gene Therapy
• Cell Cycle Regulation

Background:

• Postnatal mammalian cardiomyocytes typically silence Cyclin A2 (CCNA2), a key cell cycle regulator.
• Previous studies showed CCNA2 delivery promotes cardiac repair in animal models.
• The impact of CCNA2 gene delivery on adult human cardiomyocyte cytokinesis remained unexplored.

Purpose of the Study:

• To investigate the effect of CCNA2 gene delivery on cytokinesis in isolated adult human cardiomyocytes.
• To elucidate the transcriptional mechanisms underlying CCNA2-induced cardiomyocyte reprogramming.
• To assess the potential of CCNA2 as a therapeutic agent for cardiac regeneration.

Main Methods:

• Developed a replication-deficient adenovirus vector encoding human CCNA2 under the cardiac Troponin T promoter.
• Performed time-lapse live imaging of isolated adult human cardiomyocytes.
• Conducted single-nucleus and bulk RNA sequencing on mouse and human heart samples.

Main Results:

• CCNA2 gene delivery induced complete cytokinesis in adult human cardiomyocytes, preserving sarcomere integrity and enabling calcium mobilization.
• Single-nucleus transcriptomics revealed a subpopulation of cardiomyocytes with enriched cytokinesis and proliferative genes in CCNA2-expressing mice.
• RNA sequencing identified key reprogramming genes relevant to CCNA2-mediated effects.

Conclusions:

• CCNA2 gene delivery can restore cardiomyocyte division and promote cardiac repair in adult human cells.
• Transcriptional analysis provides insights into the mechanisms of CCNA2-induced cardiac regeneration.
• CCNA2-based gene therapy represents a promising avenue for clinical cardiac regenerative medicine.