Researchers from the Bakkers group at the Hubrecht Institute have made a significant breakthrough in heart regeneration by successfully repairing damaged mouse hearts using a protein from zebrafish. The protein, known as Hmga1, plays a crucial role in heart regeneration in zebrafish by activating dormant repair genes without causing side effects such as heart enlargement. This groundbreaking study, supported by the Dutch Heart Foundation and Hartekind Foundation, paves the way for regenerative therapies that could prevent heart failure. The findings were published in Nature Cardiovascular Research on January 2, 2025.
In humans, the heart loses millions of muscle cells after a heart attack, which cannot regrow, leading to heart failure. In contrast, zebrafish have the ability to grow new heart muscle cells and fully restore heart function within 60 days after heart damage. By studying zebrafish and comparing them to other species, researchers aim to uncover the mechanisms of heart regeneration to develop therapies that could prevent heart failure in humans. Jeroen Bakkers, the leader of the study, highlights the importance of understanding why some species can regenerate their hearts while others cannot.
The research team identified Hmga1 as the protein responsible for enabling heart repair in zebrafish. By comparing the activity of genes in damaged and healthy parts of the heart in zebrafish and mice, they found that the gene for Hmga1 is active during heart regeneration in zebrafish but not in mice, indicating its key role in heart repair. The Hmga1 protein clears molecular ‘roadblocks’ on chromatin, allowing dormant genes to become active and promote heart repair.
To test if the protein works similarly in mammals, the researchers applied Hmga1 locally to damaged mouse hearts, which resulted in stimulated heart muscle cells dividing and growing, improving heart function significantly. The cell division occurred only in the damaged area without adverse effects such as excessive growth or an enlarged heart, suggesting that damaged tissue sends a signal to activate the repair process. The comparison of Hmga1 gene activity in zebrafish, mice, and humans revealed that the protein is not produced in adult mice or humans after a heart attack, but the gene is active during embryonic development, laying the foundation for potential gene therapies.
While these findings open doors for safe, targeted regenerative therapies, further research and refinement are needed before clinical application. The next steps include testing whether the protein works on human heart muscle cells in culture, and collaboration with UMC Utrecht to explore heart regeneration further in the Summit program (DRIVE-RM) starting in 2025. This research collaboration involved scientists from the Hubrecht Institute, OUTREACH consortium, Dutch Heart Foundation, Hartekind Foundation, and various experts in mouse research, emphasizing the importance of interdisciplinary collaboration in translating discoveries from zebrafish to mice and potentially to humans.
Overall, this study on heart regeneration using a protein from zebrafish in repairing damaged mouse hearts marks a significant advancement in regenerative therapies for preventing heart failure. The identification of the Hmga1 protein’s role in heart repair, its ability to clear ‘roadblocks’ on chromatin, and its potential for unlocking the heart’s regenerative potential in humans present promising opportunities for future research and clinical applications in heart regeneration.