Zebrafish are amazing creatures. They are not only completely open, but also can grow new organs. We already knew that these transparent little fish can regenerate the retina – Now new research shows how zebrafish can regenerate heart tissue after injury.
“We wanted to know how this little fish did it and if we could learn from it,” says study author Jan Philipp Junker, a developmental biologist at the Berlin Institute for Medical Systems Biology in Germany.
Published Nature geneticsThe new study, led by Juncker and Daniela Panakova, a cell signaling researcher at the Max Delbrück Center for Molecular Medicine, describes the cascade of events that restores the zebrafish heart.
In humans, heart muscle cells called cardiomyocytes cannot regenerate like zebrafish heart cells. During a heart attack, our cardiomyocytes, deprived of oxygen, are damaged, and the lost muscle is replaced by permanent scarring (called fibrosis), making the heart weaker than before.
Zebrafish can regrow 20 percent of a millimeter heart within two months of heart injury.
This new study shows that connective tissue cells called fibroblasts are the conduits of the heart’s regeneration process in zebrafish, producing proteins that signal remodeling.
Intriguingly, the new findings join the ranks of other promising efforts in regenerative medicine, which aim to replace or repair damaged hearts with cell-based therapies or drugs that mimic molecules found in zebrafish.
Earlier this year, surgeons implanted a pig heart into a human patient for the first time (though, sadly, the man died two months later).
In May, researchers also identified human cells that help rebuild the human heart after a heart attack.
In June, scientists succeeded in “healing” heart attacks in mice using mRNA, which provides genetic instructions to the heart muscle cells of mice.
In this new study, scientists cut the tiny hearts of animals with a very cold needle to mimic a human heart attack (also known as a myocardial infarction) and see what happens.
“Surprisingly, the immediate response to injury is very similar,” Junker says. “But the process in humans stops at that point, and it continues in fish. They generate new cardiomyocytes that are able to contract.”
Using single-cell sequencing techniques, the team then scanned nearly 200,000 heart cells isolated from zebrafish, extracting genomic information from individual cells to see which were active when injured.
They identified three types of fibroblasts that enter a transiently activated state by turning on genes that encode muscle-building proteins such as collagen XII, which promote connective tissue growth.
After the researchers “silenced” those genes in the zebrafish, their hearts could not regenerate.
“They build up at the site of the wound,” Junker says of the collagen-expressing fibroblasts.
Fibroblasts may play a key role, but previous studies with zebrafish have shown that inflammatory cells called macrophages respond quickly to heart attacks and require heart regeneration.
The epicardium, the outer layer of the heart, has also been identified as a heart repair center, which this new study supports.
After engineering cells with unique genetic “barcodes,” the researchers studied activated fibroblasts and showed that they were made in the zebrafish epicardium, and only there did the cells produce collagen XII.
The single-cell sequencing techniques used by the researchers in this study to pinpoint the location of heart cells that send regenerative signals are at the forefront of rapidly evolving genomic technologies.
Although single-cell sequencing is widely used and provides unique details about the activity of a single cell, more research is needed to confirm the findings in other model organisms. It is not known whether the same fibroblast-directed mechanisms are found in mammals such as humans and mice.
“Heart regeneration is a complex process influenced by many factors,” says the author and developmental biologist Bastian Spain, as well Berlin Institute of Medical Systems Biology.
“The experiments produced an enormous amount of data. It was very difficult to filter out the correct biological signals.”
The team also wants to take a closer look at the genes that encode proteins that are turned on in activated fibroblasts, at least in zebrafish, that stimulate the regrowth of heart muscle cells.
For now, the research sheds more light on the biological processes that occur in response to a heart attack, insights that may help prevent subsequent heart events that can become dangerous after a first heart attack over time.
The study was published Nature genetics.