A team of researchers has just published a new study in Nature Genetics describing how zebrafish ( Danio rerio ) is capable of regenerating a part of the heart tissue that is damaged after suffering a heart attack. “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 Biology in Berlin.
In the case of humans, cardiomyocytes, which are the cells of the heart muscle, cannot regenerate if they are damaged. When a person has a heart attack, cardiomyocytes are deprived of oxygen, damaged, and permanent scarring (fibrosis) forms in place of the lost muscle. The heart is therefore weaker than before. Zebrafish, by contrast, can regenerate up to 20% of their tiny hearts within two months of injury.
Researchers have discovered that connective tissue cells called fibroblasts are the drivers of this heart regeneration process in zebrafish, producing proteins that act as repair signals.
The discovery comes at a time when significant efforts are being made in the field of regenerative medicine to replace or repair damaged hearts with cell therapies or drugs that mimic zebrafish molecules. In early 2022, a team of surgeons transplanted a pig’s heart into a human for the first time. However, he passed away two months later. In May, the human cells that help our hearts to “fix themselves” after a heart attack were identified. In June, scientists succeeded in “curing” a heart attack in mice with an mRNA technique that gives heart muscle cells genetic instructions to repair themselves.
In the current study, the researchers mimicked a human heart attack in fish . What they did was stick 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 form new cardiomyocytes, which are capable of contracting.”
The scientists also analyzed some 200,000 heart cells isolated from zebrafish (obtained by cell sequencing) before and after injury. They wanted to know which cells were active in the injured heart. It turned out that three types of fibroblasts temporarily entered a state of activation, turning on genes that code for muscle-building proteins like type XII collagen , which promotes the growth of connective tissue. When the researchers “silenced” those genes in zebrafish, their hearts were unable to regenerate. “After all, they form right at the site of injury,” Junker says of collagen-expressing fibroblasts.
Although fibroblasts are thought to play a key role in heart regeneration after a heart attack, previous research with zebrafish has shown that inflammatory cells called macrophages respond rapidly to heart attacks and are necessary for such regeneration.
The epicardium , which is the outer layer of the heart, has also been identified as a heart regeneration center, something this new study supports. 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 of the Institute for Medical Systems Biology in Berlin.
The team also wants to take a closer look at genes that are turned on in fibroblasts, which encode proteins that, at least in zebrafish, appear to stimulate heart muscle cell regrowth.
For now, the study sheds more light on the biological processes that take place in response to a heart attack, insights that could, over time, help prevent subsequent cardiac events that become more dangerous after the first attack.
Referencia: Hu, B., Lelek, S., Spanjaard, B. et al. 2022. Origin and function of activated fibroblast states during zebrafish heart regeneration. Nature Genetics. DOI: https://doi.org/10.1038/s41588-022-01129-5
