Zebrafish are amazing animals. They have the ability to develop new organs and are entirely transparent. New research demonstrates how zebrafish can repair heart tissue after injury. We previously knew that these transparent tiny fish could rebuild retinal tissue in their eyes.
Jan Philipp Junker, a developmental biologist at the Berlin Institute for Medical Systems Biology in Germany and the study’s lead author, says, “We wanted to understand how this small fish achieves it and see if there was anything we could learn from it.”
The latest work by Junker and Daniela Panáková, a cell signaling researcher at the Max Delbrück Center for Molecular Medicine, was published in Nature Genetics and details the series of actions that lead to zebrafish heart regeneration.
Cardiomyocytes, the cardiac muscle cells found in the heart of zebrafish, can regenerate, but not in humans. Our cardiomyocytes are harmed when we are oxygen-deprived during a heart attack, and chronic scarring (called fibrosis) takes the place of the missing muscle, making the heart weaker than it was before.
However, within two months following a heart lesion, zebrafish may recover up to 20% of their one millimeter-sized hearts.
This new research demonstrates that the zebrafish heart regeneration process is guided by connective tissue cells called fibroblasts, which also produce proteins that serve as repair signals.
The latest results are particularly exciting since they follow closely on the heels of previous promising initiatives in regenerative medicine that aim to replace or repair damaged hearts using cell-based treatments or medications that mimic chemicals found in zebrafish.
For the first time ever, doctors put a pig heart into a human patient earlier this year (though, sadly, the man died two months later).
Researchers identified the human cells that aid the human heart in self-healing after a heart attack in May.
And in June, using an mRNA approach that sends genetic instructions to cardiac muscle cells so they can mend themselves, researchers were successful in “curing” a heart attack in mice.
In this latest study, the researchers simulated a human heart attack (also known as a myocardial infarction) by zapping the animals’ tiny hearts with a very cold needle. They then observed what happened.
Surprisingly, Junker notes, “the initial reaction to the injury is extremely comparable.” “However, although in humans the process ends at that time, it continues in fish. They create brand-new cardiomyocytes that can contract.”
The scientists next examined over 200,000 isolated zebrafish heart cells using single-cell sequencing methods, gathering genetic data from each cell to determine which ones were active in a damaged heart.
They found that three different kinds of fibroblasts briefly went into an active state, activating genes that produce proteins that help develop muscles, such collagen XII, which encourages the creation of connective tissue.
And the zebrafish’s hearts did not recover when the researchers “silenced” particular genes in them.
The fibroblasts that produce collagen “form exactly at the site of damage, after all,” according to Junker.
While fibroblasts may be important, earlier zebrafish studies shown that inflammatory cells known as macrophages are quick to respond to heart assaults and necessary for heart regeneration.
This new study confirms that the epicardium, the heart’s outer layer, serves as a focal point for heart regeneration.
The researchers located the activated fibroblasts and demonstrated that they were generated in the zebrafish epicardium, and only there did the cells synthesize collagen XII, after giving the cells distinctive genetic “barcodes.”
The cutting edge of rapidly developing genomic technology is single-cell sequencing, which was employed in this work to identify cardiac cells emitting regeneration signals.
More research will be required to confirm the study results in additional model species, despite the fact that single-cell sequencing is often utilized and offers extraordinary data regarding the activity of single cells. It is unknown if animals like mice and humans exhibit the same fibroblast-driven pathways.
The study’s lead author and developmental biologist Bastiaan Spanjaard, who is also affiliated with the Berlin Institute for Medical Systems Biology, adds that heart regeneration is a complicated process that is impacted by a variety of factors.
“There was a huge amount of data generated by the experiments. Getting the right biological signals out of them was quite difficult.”
The team is particularly interested in learning more about the genes that are turned on in active fibroblasts and that encode proteins that, at least in zebrafish, appear to drive the growth of heart muscle cells.
For the time being, the study provides further insight into the biochemical processes taking place after a heart attack, providing knowledge that might one day assist prevent recurrent cardiac occurrences that grow riskier following the initial attack.