For decades, cardiologists have known that the human heart stops producing new muscle cells shortly after birth, leaving no way to replace those lost to heart attack or failure. However, a new study published in npj Regenerative Medicine, led by Hina Chaudhry, MD, director of Cardiovascular Regenerative Medicine at the Icahn School of Medicine at Mount Sinai, shows that the gene for Cyclin A2 (CCNA2), silenced early in life, can be switched back on to make adult heart cells divide again—without losing their structure or function.
In earlier animal work, Chaudhry’s team achieved the first regeneration of a large mammalian heart, showing that reintroducing CCNA2 could restore cardiac function after myocardial infarction in pigs, whose hearts resemble those of humans. The new human-focused study provides a critical translational step, demonstrating that adult cardiomyocytes from donor hearts can be safely induced to divide and form new, functional daughter cells.
Gene therapy approach to regeneration
Using a human-compatible viral vector, the researchers delivered CCNA2 directly into adult cardiomyocytes isolated from donor hearts aged 21, 41, and 55 years. Time-lapse microscopy captured the reactivation of the cell cycle: in the 41- and 55-year-old hearts, muscle cells rounded up and split into two viable daughter cells while preserving their sarcomere structure—the contractile machinery essential for heart function. Calcium-imaging studies confirmed that the new cells remained electrically active.
The team observed no division in 21-year-old cells, consistent with earlier evidence that younger adult hearts retain some baseline regenerative ability. “Even middle-aged adult human heart cells—long believed incapable of division—can be coaxed back into making new, functional cells,” Chaudhry said. “This shifts the paradigm from managing symptoms to actually repairing the human heart.”
How Cyclin A2 rewires cell identity
By integrating single-nucleus transcriptomics from CCNA2-expressing mouse hearts with ultra-deep RNA sequencing of fetal and adult human hearts, the study reveals how Cyclin A2 briefly reverts cardiomyocytes to a regenerative, fetal-like state. Cells expressed gene networks linked to cytokinesis, calcium handling, and sarcomere remodeling, while maintaining contractile integrity.
Importantly, this transient reprogramming did not produce immature or fibrotic tissue—a major obstacle in earlier regeneration efforts. Instead, CCNA2 created a controlled window of proliferation, enabling division without losing differentiated identity.
Toward clinical translation
Mechanistically, CCNA2 appears to act as a master regulator of cardiomyocyte division. The gene reactivates key cell-cycle effectors that have been silenced in adult hearts, allowing cells to duplicate their centrosomes and proceed through mitosis without losing their structural integrity.
Unlike prior strategies that push cells into incomplete replication or trigger hypertrophic stress, Cyclin A2 produces orderly, symmetric cell division. The process is self-limiting: once division is complete, CCNA2 activity declines, suggesting a built-in safety mechanism that could minimize oncogenic risk.
Because the therapy relies on a clinically compatible viral vector, the researchers envision translating it into a gene therapy delivered via intracoronary infusion—similar to how other cardiac vectors are administered during catheterization. The goal is to stimulate regeneration in the border zones surrounding heart attack scars, improving function without replacing the entire organ.
Broader implications for regenerative medicine
By demonstrating that human heart cells can re-enter the cell cycle when given the right molecular cue, the study challenges the long-held view that the adult myocardium is terminally post-mitotic. It also raises intriguing questions about other organs long considered non-regenerative, such as the brain or pancreas.
Chaudhry’s team is now preparing preclinical safety and toxicology studies required for FDA approval to begin early human trials. If successful, CCNA2 therapy could provide a regenerative alternative to heart transplantation or mechanical assist devices.
“Our goal is to deliver a therapy that allows the heart to heal itself after a heart attack or in heart failure—reducing the need for transplants or mechanical devices,” said Chaudhry.
