Scientists at the Hubrecht Institute in the Netherlands have achieved a remarkable breakthrough in heart regeneration therapy. By utilizing a protein found in zebrafish, known as Hmga1, they successfully repaired damaged mouse hearts, paving the way for potential treatments to prevent heart failure in humans.
After a heart attack, humans lose millions of heart muscle cells that cannot regrow, often leading to heart failure where the heart struggles to pump blood effectively. In stark contrast, zebrafish possess an extraordinary ability to regenerate their hearts, fully restoring function within 60 days of injury.
"We don't understand why some species can regenerate their hearts after injury while others cannot," said Professor Jeroen Bakkers, who led the study at the Hubrecht Institute. "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."
The research team, including first author Dennis de Bakker, identified the Hmga1 protein as a key player in heart repair. "We compared the zebrafish heart to the mouse heart, which, like the human heart, cannot regenerate," explained de Bakker. "We looked at the activity of genes in damaged and healthy parts of the heart."
Their 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," said de Bakker.
Hmga1 is typically important during embryonic development when cells need to grow extensively. In adult cells, however, the gene for Hmga1 is usually turned off. The researchers sought to understand how this protein functions in heart regeneration.
"We discovered that Hmga1 removes molecular 'roadblocks' on chromatin," explained co-first author Mara Bouwman. Chromatin is the structure that packages DNA. When it is tightly packed, genes are inactive. "Hmga1 clears the way, so to say, allowing dormant genes to get back to work," she added.
To test whether Hmga1 could have the same effect in mammals, the team applied the protein locally to damaged mouse hearts. "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 of the mouse hearts. "There were no adverse effects, such as excessive growth or an enlarged heart," emphasized Bouwman. "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."
The gene for Hmga1 is present in humans and active during embryonic development. However, in adult human hearts, the Hmga1 protein is not produced after a heart attack. "This provides a foundation for gene therapies that could unlock the heart's regenerative potential in humans," Bakkers explained.
While these findings are promising, the researchers acknowledge that there's still much work to be done. "We need to refine and test the therapy further before it can be brought to the clinic," said Bakkers. "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."
This groundbreaking research was a collaborative endeavor. "Normally, our group only focuses on zebrafish," noted Bouwman. "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," she continued. "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."
The study, titled Cross-Species Comparison Reveals Hmga1 Reduces H3K27me3 Levels to Promote Cardiomyocyte Proliferation and Cardiac Regeneration, was published in Nature Cardiovascular Research. The research was conducted as part of the OUTREACH consortium and funded by the Dutch Heart Foundation and Hartekind Foundation.
This article was written in collaboration with generative AI company Alchemiq