Researchers from the Bakkers group at the Hubrecht Institute have successfully repaired
damaged mouse hearts using a protein from zebrafish. They discovered that the protein Hmga1
plays a key role in heart 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, supported by the Dutch Heart Foundation and Hartekind Foundation,
marks an important step toward regenerative therapies to prevent heart failure. The findings
were published in Nature Cardiovascular Research on January 2, 2025.
After a heart attack, the human heart loses millions of muscle cells that cannot regrow. This
often leads to heart failure, where the heart struggles to pump blood effectively. Unlike humans,
zebrafish grow new heart muscle cells: they have a regenerative capacity. When a zebrafish
heart is damaged, it can fully restore its function within 60 days. “We don’t understand why
some species can regenerate their hearts after injury while others cannot,” explains Jeroen
Bakkers, the study’s leader. “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.”
A Protein That Repairs Damage
The research team identified a protein that enables heart repair in zebrafish. “We compared the
zebrafish heart to the mouse heart, which, like the human heart, cannot regenerate,” says
Dennis de Bakker, the study’s first author. “We looked at the activity of genes in damaged and
healthy parts of the heart,” he explains. “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.” Typically, 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 turned off.
Clearing ‘Roadblocks’
The researchers investigated how the Hmga1 protein works. “We discovered that Hmga1
removes molecular ‘roadblocks’ on chromatin,” explains Mara Bouwman, co-first author.
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,” she adds.
From Fish to Mammals
To test if the protein works similarly in mammals, the researchers applied it locally to damaged
mouse hearts. “The results were remarkable: the Hmga1 protein stimulated heart muscle cells
to divide and grow, significantly improving heart function,” says 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,” Bouwman emphasizes. “This suggests that the damage itself
sends a signal to activate the process.”
The team then 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 gene for Hmga1 is present in humans and active during embryonic development.
“This provides a foundation for gene therapies that could unlock the heart’s regenerative
potential in humans,” Bakkers explains.
The Broader Impact of Heart Regeneration Research
The findings from the Bakkers group represent a significant milestone in understanding the
molecular mechanisms of heart regeneration. While heart failure remains a leading cause of
mortality and morbidity worldwide, the ability to repair damaged heart tissue could transform the
treatment landscape. Current therapies for heart failure focus primarily on managing symptoms,
such as using medications to reduce fluid buildup or improve heart function. However, they do
not address the root cause: the loss of heart muscle cells. The introduction of regenerative
therapies, like those inspired by zebrafish biology, could provide a way to restore the heart’s
structure and function, offering hope to millions of patients.
Moreover, the discovery of Hmga1’s role highlights how evolutionary differences between
species can guide medical advancements. Zebrafish are often used as models in scientific
research because of their unique regenerative abilities and genetic similarities to humans. While
their hearts can regenerate after injury, mammals, including humans, lack this capability. This
stark contrast underscores the potential for cross-species studies to reveal dormant pathways
that could be reactivated for therapeutic purposes.
Challenges and Future Directions
Despite these promising findings, there are still challenges to address before the Hmga1-based
therapy can be translated to human patients. First, scientists must ensure that activating Hmga1
in human heart cells will not trigger unintended consequences, such as uncontrolled cell growth
or cancer. Although the current study found no adverse effects in mice, human biology is more
complex, and long-term safety must be rigorously evaluated.
Another challenge involves the delivery method for Hmga1. In the mouse study, the protein was
applied locally to the heart. For human patients, researchers will need to develop a reliable and
minimally invasive delivery system, such as an injectable gene therapy or nanoparticles capable
of targeting damaged heart tissue. Advances in biocompatible materials and precision medicine
could play a critical role in overcoming this hurdle.
Furthermore, regulatory approval and clinical trials will require years of additional research and
development. Scientists will need to demonstrate not only safety but also consistent efficacy
across diverse patient populations. The cost and accessibility of such therapies will also be
important considerations, particularly in low-resource settings where the burden of
cardiovascular disease is often the highest.
What’s Next?
These findings open doors for safe, targeted regenerative therapies, but there is still much work
to do. “We need to refine and test the therapy further before it can be brought to the clinic,” says
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.”
In addition to testing the therapy on human cells, researchers plan to explore whether Hmga1
can stimulate regeneration in other tissues. The protein’s ability to remove chromatin roadblocks
and activate dormant genes could have applications beyond the heart. For example, it might be
used to treat injuries to the brain, spinal cord, or other organs where regeneration is limited.
Heart for Collaboration
This research brought together scientists from the Hubrecht Institute and beyond. It was
conducted as part of the OUTREACH consortium and funded by the Dutch Heart Foundation
and Hartekind Foundation. The OUTREACH consortium is a collaboration between research
institutes and all academic hospitals involved in treating patients with congenital heart defects in
the Netherlands. “Normally, our group only focuses on zebrafish,” says 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.”
The spirit of collaboration is vital in advancing medical research. The integration of expertise
from different disciplines, such as genetics, developmental biology, and clinical cardiology,
ensures that findings are robust and broadly applicable. This multidisciplinary approach is
especially important in regenerative medicine, where the ultimate goal is to translate basic
scientific discoveries into real-world treatments that improve patients’ lives.
A Hopeful Outlook
As the global population ages and the prevalence of cardiovascular diseases rises, the need for
innovative treatments becomes increasingly urgent. Regenerative therapies based on the
principles of heart repair in zebrafish could revolutionize the field of cardiology. While significant
hurdles remain, the discovery of Hmga1’s role in heart regeneration offers a beacon of hope.
With continued research and collaboration, the dream of repairing a damaged human heart may
soon become a reality, ushering in a new era of precision medicine and improved outcomes for
millions of patients worldwide.