Researchers from the Hubrecht Institute and their collaborators at other institutions have used a protein from zebrafish dubbed Hmga1 which plays a key role in heart regeneration, to reactivate heart repair genes in mice. The protein successfully restored the heart by modulating epigenetic modifications without causing harmful side effects such as an enlarged heart.
Full details are provided in a new Nature Cardiovascular Research paper titled “Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.”
The findings point to the possibility of developing regenerative therapies for human patients that leverage the epigenome. Zebrafish are one of several model organisms that scientists use in regenerative studies. Unlike humans, zebrafish grow new heart muscle cells and can fully restore the function of a damaged heart within 60 days. It’s a mechanism that’s not fully understood but 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,” said Jeroen Bakkers, PhD, group leader at the Hubrecht Institute, professor of molecular cardiogenetics at University Medical Center Utrecht, and study leader.
Like humans, mouse hearts cannot regenerate. For this study, “we looked at the activity of genes in damaged and healthy parts of the heart” in both mouse and zebrafish, Dennis de Bakker, PhD, the study’s first author, explained. The Hmga1 gene is usually active during embryonic development but turned off in adult cells.
However, the protein is active during heart regeneration in zebrafish but not in mice suggesting that Hmga1 plays a key role in heart repair. Specifically, “Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program,” the researchers wrote in the paper. In other words, it “removes molecular ‘roadblocks’ on chromatin”, explained Mara Bouwman, PhD, co-first author on the paper. “Hmga1 clears the way, so to say, allowing dormant genes to get back to work.”
To test if the protein works the same way in mammals as it does in zebrafish, the researchers applied it locally to damaged mouse hearts. They found that the protein stimulated damaged heart muscle cells to divide and grow. And the effect only occurred in the damaged area with no adverse effects to healthy heart tissue. It suggests that the damage sends a specific signal to activate the process.
Next the team compared Hmga1 gene activity in zebrafish, mice, and humans. As it turns out, in adult human and mouse hearts, the protein is not produced after damage occurs. But since the gene is present and active during embryonic development, it may be possible to develop gene therapies that can reactivate protein production when adult hearts are damaged. “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.”
