“We wanted to find out how this little fish does it, and if we can learn from it,” says developmental biologist and study author Jan-Philip Juncker of the Berlin Institute for Medical Systems Biology in Germany.
Posted in natural geneticsThe new study that Juncker led with Daniela Panakova, a cell signaling researcher at the Max Delbrück Center for Molecular Medicine, chronicles the chain of events that led to cardiac regeneration in zebrafish.
In humans, heart muscle cells called cardiomyocytes cannot regenerate like zebrafish heart cells. Due to a lack of oxygen during a heart attack, heart muscle cells are damaged, and permanent scarring (called fibrosis) forms instead of the missing muscle, making the heart weaker than it was before.
However, zebrafish are able to regrow up to 20 percent of their one-millimeter hearts within two months of heart injury.
What this new study shows us is that connective tissue cells called fibroblasts are the conductors of the heart regeneration process in zebrafish, producing proteins that act as repair signals.
Impressively, the new findings come hot with other promising efforts in regenerative medicine — looking to either replace or repair damaged hearts with cell-based therapies or drugs that mimic molecules found in zebrafish.
Earlier this year, surgeons transplanted a pig’s heart into a human patient for the first time (although the man unfortunately died two months later).
In May, researchers also identified the human cells that help the human heart repair itself after a heart attack.
And in June, scientists successfully treated heart attacks in mice with an mRNA technique that provides genetic instructions for heart muscle cells to repair themselves.
In this new study, researchers stun young animals’ hearts with a very cold needle to mimic a human heart attack (also called a myocardial infarction) and watched what happened.
“Surprisingly, the immediate response to injury is very similar,” Juncker says. “But while the process stops in humans at this point, it continues in fish. It forms new muscle cells that are able to contract.”
Using single-cell sequencing techniques, the team then examined about 200,000 isolated heart cells from zebrafish before and after injury, extracting genetic information from individual cells to see which ones were active in the damaged heart.
They discovered three types of fibroblasts temporarily entered an active state, turning on genes that encode muscle-building proteins such as collagen XII, which promotes connective tissue growth.
And when the researchers ‘silenced’ those genes in zebrafish, their hearts could no longer regenerate.
Juncker says of the collagen-expressing fibroblasts:
While fibroblasts may play a key role, previous research in zebrafish has shown that inflammatory cells called macrophages are rapid responders to heart attacks and are required for heart regeneration.
The epicardium, the outermost layer of the heart, has been identified as a hub for cardiac regeneration, something this new study supports.
After engineering the cells with unique genetic “barcodes,” the researchers traced the activated fibroblasts and showed that they were made in zebrafish toasts, and only there the cells produced XII collagen.
Single-cell sequencing techniques, which the researchers used in this study to identify heart cells that send out regenerative signals, are at the forefront of rapidly advancing genomic technologies.
Although single-cell sequencing is widely used and provides exceptional details about single-cell activity, further research will be required to validate the study results in other model organisms. It is unclear whether the same mechanisms driven by fibroblasts are also present in mammals such as humans and mice.
“Heart regeneration is a complex process that is affected by many different things,” says the study’s author and developmental biologist. Bastian Spangard, too Berlin Institute for Medical Systems Biology.
“The experiments produced huge amounts of data. Filtering out the correct biological signals from them was very difficult.”
The team also wants to look more closely at the genes that are turned on in activated fibroblasts, encoding proteins that — at least in zebrafish — appear to stimulate cardiomyocytes to regrow.
For now, the study sheds more light on the biological processes that occur in response to a heart attack, insights that, in time, may help stave off later cardiac events that become more serious after the first attack.
The study was published in natural genetics.