Posted on 14 January 2025
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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
The problem:
Cardiovascular diseases remain the leading cause of death worldwide, accounting for around 18.5 million deaths a year. During a myocardial infarction (MI), more commonly known as a heart attack, a portion of the heart muscle is deprived of blood due to the obstruction of a coronary artery. This causes many cardiomyocytes (heart muscle cells) to die. Unfortunately, adult humans lack the ability to regenerate these cells, and so the damaged tissue is instead replaced with fibrotic scar tissue. This tissue stiffens the heart and forms a barrier to the waves of electricity that make the heart beat, increasing the likelihood of further cardiac problems.
Unlike mammals, adult zebrafish hearts are capable of replacing lost cardiomyocytes after injury. In this study, researchers investigate what mechanisms drive this regeneration, with the hope that we might one day be able to harness them to repair damaged human hearts.
The discovery:
Researchers conducted a cross-species comparison to uncover the mechanisms driving heart regeneration. First, they compared gene activity in injured hearts of zebrafish and mice. They identified a selection of genes responsible for the changes that occur in zebrafish cardiomyocytes when an injury occurs. These changes include increased proliferation and switching to a more stem cell-like state. Moreover, they found that the activity of these genes was controlled by a protein called Hmga1.
Hmga proteins work by competing with the structural proteins (called histones) around which the DNA is wrapped. During development, regions of the DNA within each cell are coiled and compacted, locking away the genes that are unnecessary for the functioning of that cell type. By competing with histones, Hmga1 decompacts the DNA and makes stem cell-related genes more accessible.
The researchers then used an adeno-associated virus (AAV) in order to boost Hmga1 expression in adult mice with cardiac injuries. This not only led to enhanced proliferation of cardiomyocytes in areas surrounding the injury, but also improved heart function. By 42 days post-injury, the ejection fraction (the proportion of blood expelled by the left ventricle at each contraction) was significantly higher in treated mice compared to untreated mice, though still significantly worse than in uninjured mice.
The implications:
The discovery that Hmga1 alone is enough to restore some of the regenerative ability of the heart is encouraging. By replicating the natural regenerative abilities of the zebrafish using gene therapy, it may be possible to enhance heart regeneration in adult humans and improve recovery after heart attacks. The treatment did not appear to cause any unforeseen adverse effects in the mice, but more animal research and a more thorough understanding of the mechanisms behind Hmga1 will be required before anything like this can be tested in humans.
Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration https://doi.org/10.1038/s44161-024-00588-9
Title image by Wirestock, Freepik
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