Scientists have identified a zebrafish protein that activates dormant genes for heart repair, marking a major breakthrough in regenerative therapies for heart disease.
Key Points at a Glance
- Hmga1 Protein: Critical for heart regeneration in zebrafish and activates dormant repair genes in mammals.
- Selective Action: Stimulates repair only in damaged heart tissue, avoiding adverse effects like enlargement.
- Potential Therapies: Opens pathways for gene-based regenerative treatments for human heart failure.
- Collaboration: Multidisciplinary teams are advancing the research toward clinical application.
The Challenge of Heart Failure
Heart attacks often result in the loss of millions of muscle cells in the heart, which human bodies cannot naturally regenerate. This leads to heart failure, where the heart struggles to pump blood effectively. In contrast, zebrafish possess an extraordinary ability to regrow heart muscle cells, fully restoring their heart function within 60 days of damage.
A recent study by researchers at the Hubrecht Institute has identified a key protein, Hmga1, which enables this regenerative process. By unlocking dormant repair genes, this protein has shown promising results in repairing damaged hearts in mice.
Decoding Heart Regeneration
The research team compared heart tissue from zebrafish and mice, focusing on gene activity in damaged and healthy areas. In zebrafish, the Hmga1 protein was active during regeneration, whereas in mice and humans, the gene for Hmga1 is dormant in adults.
“Hmga1 is essential during embryonic development, when cells need to grow rapidly,” explains Dennis de Bakker, the study’s first author. “In adults, the gene is turned off, but it holds the key to unlocking the heart’s regenerative potential.”
How Hmga1 Works
The Hmga1 protein functions by clearing molecular “roadblocks” on chromatin, the structure that packages DNA. These roadblocks keep repair genes inactive by tightly packing the DNA. Hmga1 loosens this packaging, reactivating genes essential for cell growth and repair.
In zebrafish, this process enables the heart to regenerate seamlessly. In mammals, introducing the Hmga1 protein locally to damaged mouse hearts achieved remarkable results.
Testing in Mammals
When applied to mouse hearts, the Hmga1 protein activated cell division and growth exclusively in damaged areas, significantly improving heart function without adverse effects. “There was no cell division in healthy tissue, and we observed no heart enlargement,” emphasizes Mara Bouwman, co-first author of the study.
This targeted repair process suggests that the injury itself signals the activation of regenerative pathways, a mechanism that could be harnessed in human therapies.
Toward Human Application
Although the Hmga1 protein is dormant in adult humans, its gene remains present and active during embryonic development. This discovery provides a foundation for developing gene therapies to reactivate the heart’s regenerative capacity.
The next phase involves testing the protein on human heart muscle cells in a laboratory setting, in collaboration with UMC Utrecht. The Summit program (DRIVE-RM), launching in 2025, aims to advance heart regeneration research.
Collaborative Efforts
This groundbreaking research was made possible by the combined expertise of teams studying zebrafish, mice, and human cells. Collaborators from the Hubrecht Institute, Amsterdam UMC, and other institutions contributed to the study, funded by the Dutch Heart Foundation and Hartekind Foundation.
The Road Ahead
While this research marks a significant step forward, extensive testing and refinement are required before these therapies can be used in clinical settings. “We are optimistic about the potential of this work,” says study leader Jeroen Bakkers. “By translating insights from zebrafish to humans, we are paving the way for regenerative therapies to combat heart failure.”
