Zebrafish Protein Promotes Cardiac Repair in Mice

Researchers from the Hubrecht Institute's Bakkers group have used a zebrafish protein to successfully repair damaged mouse hearts. The team found that zebrafish heart regeneration is significantly influenced by the protein Hmga1. This protein activated dormant repair genes in mice, restoring the heart without causing adverse effects like heart enlargement. The study was published in Nature Cardiovascular Research.

This study represents a significant advancement in the development of regenerative treatments for the prevention of heart failure with funding from the Dutch Heart Foundation and Hartekind Foundation.

Millions of muscle cells in the human heart are lost after a heart attack and cannot be replaced. Heart failure, in which the heart finds it difficult to pump blood efficiently, is frequently the result of this. Zebrafish have the ability to regenerate their heart muscle cells, unlike humans. Within 60 days, a damaged zebrafish heart can fully recover its function.

We don’t understand why some species can regenerate their hearts after injury while others cannot. By studying zebrafish and comparing them to other species, we can uncover the mechanisms of heart regeneration. This could eventually lead to therapies to prevent heart failure in humans.”

Jeroen Bakkers, Study Leader, Hubrecht Institute

A Protein That Repairs Damage

The scientists discovered a protein that helps zebrafish heal their hearts.

We compared the zebrafish heart to the mouse heart, which, like the human heart, cannot regenerate. We looked at the activity of genes in damaged and healthy parts of the heart. Our findings revealed that the gene for the Hmga1 protein is active during heart regeneration in zebrafish but not in mice. This showed us that Hmga1 plays a key role in heart repair.”

Dennis de Bakker, Study First Author, Hubrecht Institute

The Hmga1 protein is generally crucial for embryonic development when cells must proliferate rapidly. The gene for this protein, however, is inactive in adult cells.

Clearing “Roadblocks”

The function of the Hmga1 protein is examined by the researchers.

We discovered that Hmga1 removes molecular ‘roadblocks’ on chromatin. Chromatin is the structure that packages DNA. When it is tightly packed, genes are inactive. When it unpacks, genes can become active again. Hmga1 clears the way, so to say, allowing dormant genes to get back to work.”

Mara Bouwman, Study Co-first Author, Hubrecht Institute

From Fish to Mammals

The scientists applied the protein locally to injured mouse hearts to see if it functions similarly in mammals.

“The results were remarkable: the Hmga1 protein stimulated heart muscle cells to divide and grow, significantly improving heart function,” said Bakkers.

Surprisingly, cell division occurred only in the damaged area—precisely where repair was needed. “There were no adverse effects, such as excessive growth or an enlarged heart. We also didn’t see any cell division in healthy heart tissue. This suggests that the damage itself sends a signal to activate the process,” emphasized Bouwman.

The Hmga1 gene's activity in zebrafish, mice, and humans was then compared by the team. Similar to adult mice, human hearts do not produce the Hmga1 protein following a heart attack. Nonetheless, humans possess the Hmga1 gene, which is active during embryonic development.

“This provides a foundation for gene therapies that could unlock the heart’s regenerative potential in humans,” explained Bakkers.

What’s Next?

Although there is still much to be done, these findings pave the way for safe, focused regenerative therapies. “We need to refine and test the therapy further before it can be brought to the clinic. The next step is to test whether the protein also works on human heart muscle cells in culture. We are collaborating with UMC Utrecht for this, and in 2025, the Summit program (DRIVE-RM) will begin to explore heart regeneration further,” said Bakkers.

Heart for Collaboration

Scientists from the Hubrecht Institute and other institutions collaborated on this study. The Dutch Heart Foundation and Hartekind Foundation provided funding for the study, which was carried out as a component of the OUTREACH consortium. Research institutes and all academic hospitals in the Netherlands that treat patients with congenital heart defects have joined forces to form the OUTREACH consortium.

“Normally, our group only focuses on zebrafish. But to understand how our findings could be applied to mammals, we collaborated with the Van Rooij group and Christoffels group (Amsterdam UMC), experts in mouse research. Thanks to the Single Cell Core at the Hubrecht Institute, we were able to study heart regeneration at a detailed level,” said Bouwman.

“We’re very lucky that we were able to set up these collaborations. It allows us to translate discoveries from zebrafish to mice and, hopefully, eventually to humans. We are learning so much from the zebrafish and its remarkable ability to regenerate its heart,” continued Bouwman.