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26 July 2022
The zebrafish (Danio rerio) is able to regenerate a damaged area of the heart tissue after suffering a heart attack, according to a recent study that has just been published in Nature Genetics. "We wanted to find out how this little fish does it and if we could learn from it," explains biologist and study author Jan Philipp Junker of the Institute for Medical Systems.
Cardiomyocytes, the cells that make up the heart muscle, cannot regenerate if they are damaged in humans. Cardiomyocytes suffer oxygen deprivation and injury during a heart attack, and persistent scarring (fibrosis) replaces the destroyed muscle. As a result, the heart is less strong than before. In contrast, two months after an injury, zebrafish can regenerate up to 20% of their small hearts.
The zebrafish heart regeneration process is driven by connective tissue cells called fibroblasts, which also produce proteins that serve as repair signals.
The discovery is timely because major attempts are currently being undertaken in the field of regenerative medicine to replace or repair damaged hearts using cell treatments or medications that imitate zebrafish chemicals. The first human heart transplant from a pig was performed on a patient in early 2022 by a team of doctors. However, he passed away two months later. The human cells that assist our hearts in "fixing themselves" following a heart attack were discovered in May. In June, scientists succeeded in "curing" a heart attack in mice with an mRNA approach that provides cardiac muscle cells with genetic instructions to repair themselves.
In the current study, the researchers mimicked a human heart attack in fish. What they did was insert an ultra-cold needle into their hearts and see what happened. "Surprisingly, the immediate response to injury is very similar," says Junker. "But whereas in humans the process stops at that point, in fish it continues. They create new cardiomyocytes that can contract.
The scientists also analyzed by cell sequencing 200,000 heart cells isolated from zebrafish before and after injury. They wanted to know which cells were active in the injured heart. It turned out that genes encoding muscle-building proteins like type XII collagen, which encourages the formation of connective tissue, were momentarily activated by three different types of fibroblasts. When the researchers "silenced" those genes in zebrafish, their hearts were unable to regenerate. "After all, they form right at the injury site," Junker says of collagen-expressing fibroblasts.
Although it is often believed that fibroblasts are essential for heart regeneration following a heart attack, previous zebrafish research has demonstrated that inflammatory cells called macrophages respond quickly to heart attacks and are required for such regeneration.
This new study supports the notion that the epicardium, the heart's outer layer, serves as a center for heart regeneration. After engineering cells with unique genetic "barcodes", the researchers tracked activated fibroblasts and showed that they were produced in the epicardium of zebrafish, and only there did the cells produce type XII collagen.
Single-cell sequencing techniques, such as those used in this study to locate heart cells that send regenerative signals, are currently at the forefront of genomic technologies. However, further research is needed to validate the study's findings in other model organisms, as it is unclear whether the same fibroblast-driven mechanisms are also found in mammals such as humans and mice.
"Heart regeneration is a complex process that is influenced by many different things," says study author and developmental biologist Bastiaan Spanjaard, also affiliated with the Institute for Medical Systems Biology in Berlin.
The group is particularly interested in learning more about genes that are active in fibroblasts because they produce proteins that, at least in zebrafish, appear to promote the rebuilding of heart muscle cells.
For the time being, the study provides further insight into the biological processes that occur in reaction to a heart attack. These insights may eventually help prevent recurrent cardiac episodes that become more dangerous following the initial attack.
Reference: Hu, B., Lelek, S., Spanjaard, B. et al. Origin and function of activated fibroblast states during zebrafish heart regeneration. Nat Genet (2022). https://doi.org/10.1038/s41588-022-01129-5