After a heart attack, the human heart loses millions of muscle cells that cannot regenerate. This often leads to heart failure, in which the heart has difficulty pumping blood effectively. Unlike humans, zebrafish generate new cardiac muscle cells. When a zebrafish’s heart is damaged, You can fully regain function in 60 days. Could this regenerative capacity be transferred to other species?
Researchers from the Bakkers group at the Hubrecht Institute have managed to repair damaged mouse hearts using the Hmga1 protein, which plays a key role in cardiac regeneration in zebrafish. In mice, this protein was able to restore the heart by activating dormant repair genes without causing side effects such as heart enlargement. This study, funded by the Dutch Heart Foundation and the Hartekind Foundation, marks an important step towards regenerative therapies to prevent heart failure. The findings are published this Thursday in Nature Cardiovascular Research.
“We don’t understand why some species can regenerate their hearts after injury while others cannot. By studying zebrafish and comparing them with other species, we can discover the mechanisms of cardiac regeneration. This could lead to therapies to prevent heart failure in humans,” explains Jeroen Bakkers, the leader of the study.
The research team first identified a protein that enables heart repair in zebrafish. «We compared the heart of the zebrafish with that of the mouse, which, like the human heart, cannot regenerate. We look at gene activity in the damaged and healthy parts of the heart. Our findings revealed that the Hmga1 protein gene is active during cardiac regeneration in zebrafish, but not in mice. “This showed us that Hmga1 plays a key role in cardiac repair,” explains Dennis de Bakker, first author of the study. Normally, the Hmga1 protein is important during embryonic development, when cells need to grow a lot. However, in adult cells, the gene for this protein is deactivated.
The researchers studied the functioning of the Hmga1 protein. «We discovered that Hmga1 removes molecular obstacles of the chromatin. Hmga1 opens the way, so to speak, allowing latent genes to work again,” explains Mara Bouwman, co-lead author. Chromatin is the structure that packages DNA. When it is very compact, the genes are inactive. When it is decompressed, the genes can be activated again.
From fish to mammals
To test whether the protein works similarly in mammals, the researchers applied it locally to damaged mouse hearts. “The results were surprising: the Hmga1 protein stimulated the division and growth of cardiac muscle cells, significantly improving cardiac function,” says Bakkers.
Surprisingly, cell division occurred only in the damaged area, precisely where repair was necessary. «There were no adverse effectssuch as excessive growth or enlargement of the 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,” emphasizes Bouwman.
The team compared the activity of the Hmga1 gene in zebrafish, mice and humans. In human hearts, as in adult mice, the Hmga1 protein is not produced after a heart attack. However, the Hmga1 gene is present in humans and is active during embryonic development. “This provides a basis for gene therapies that could unlock the regenerative potential of the heart in humans,” explains Bakkers.
These findings open the door to safe regenerative therapies and specific, but there is still a lot of work to do. “We need to refine and test the therapy further before we can take it to the clinic. The next step is to test whether the protein also works in cultured human cardiac muscle cells. We are collaborating with UMC Utrecht for this, and in 2025, the Summit program (DRIVE-RM) will begin to further explore cardiac regeneration,” says Bakkers.
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