In a new study published in Nature Regenerative Medicine titled, “Cyclin A2 induces cytokinesis in human adult cardiomyocytes and drives reprogramming in mice,” researchers from Icahn School of Medicine at Mount Sinai have shown that the gene for Cyclin A2 (CCNA2), which turns off after birth in humans, can promote cardiac repair in adult human cardiomyocytes, providing a new avenue to treat heart injury and failure as an alternative to heart transplants or implanted cardiac devices.
This work builds on the 2014 work of Hina Chaudhry, MD, director of Cardiovascular Regenerative Medicine at Mount Sinai and corresponding author of the study, which demonstrated heart regeneration of a large mammal (pig) after a heart attack by reactivating CCNA2. The new study shows a translational bridge, in which a human-compatible viral vector can safely and effectively trigger cell division in adult human heart cells.
“Heart disease is the leading cause of death worldwide, yet adult human heart muscle cells stop dividing after birth,” Chaudhry said. “Our work was the first to show that we can regenerate the porcine heart after injury, and now we’ve advanced the field by demonstrating that even middle-aged adult human heart cells—long believed incapable of division—can be coaxed back into making new, functional cells. This shifts the paradigm from managing symptoms to actually repairing the human heart.”
The research team built a replication-deficient human-compatible virus that delivers the CCNA2 to heart muscle cells from healthy donor hearts. Using time-lapse imaging, the results showed that heart cells with CCNA2 and divided successfully, while maintaining their normal structure and function.
Notably, the authors analyzed three healthy hearts from donors who were 21, 41, and 55-years-old. Cyclin A2 therapy triggered human heart cells to divide in the 41- and 55-year-old hearts. Conversely, cells from hearts belonging to a 21-year-old showed no change when given the CCNA2 therapy. This finding aligns with previous studies that suggest younger hearts have regenerative potential and are capable of dividing without the stimulus provided by CCNA2.
Additionally, daughter cells, or cells resulting from cell division, retained their structural proteins and normal calcium activity, indicating that they remain functional. Further analysis showed that CCNA2 helps heart cells briefly reactivate certain growth genes to allow heart repair. Notably, this process does not make the cells immature or cause the harmful thickening of heart tissue seen in disease.
“This is the culmination of nearly two decades of work,” said Chaudhry. “We pioneered the concept that the heart could be regenerated by reawakening dormant cell division genes, and now we’ve brought that vision one step closer to patients. 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.”
The next step will seek FDA approval to begin clinical trials of CCNA2 therapy in patients with heart disease.
