How a Certain Animal Can Regenerate a Broken Heart



Research led by Jan Philipp Junker and Daniela Panáková at the MDC suggests that zebrafish may be able to heal damaged cardiac tissue.

Cardiomyocytes, the cells that make up the heart muscle, suffer damage from a lack of oxygen and start to die when a person has a heart attack and does not receive timely medical attention. Since we are unable to produce new cardiomyocytes, scar tissue develops and the heart's ability to pump is reduced. Lower vertebrates, like the zebrafish, which can regenerate organs including its heart, experience a fundamentally different world.

Professor Jan Philipp Junker, head of the Quantitative Developmental Biology Lab at the Berlin Institute for Medical Systems Biology (BIMSB), a division of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, says, "We wanted to find out how this little fish does that, and if we could learn from it.

With the assistance of Dr. Daniela Panáková, who is the director of the Electrochemical Signaling in Development and Disease Lab at the MDC, the researchers mimicked myocardial infarction lesions in the hearts of their zebrafish. They used cell lineage trees and single-cell studies to track the regeneration of the cardiomyocytes. Recent publication of their findings in Nature Genetics.

Zebrafish adults viewed via a brightfield microscope. Zebrafish heart 7 days after cryoinjury, on the left. Fibroblasts that are momentarily triggered focus on the site of the injury. Image source: Panáková Lab, MDC

Human hearts are incapable of regenerating.

The researchers used a microscope to study the one-millimeter zebrafish heart, which was briefly exposed to a chilly needle. The needle killed any tissue it touched. Similar to people who have experienced a heart attack, this causes an inflammatory reaction, which is followed by scarring made by fibroblasts.

The immediate reaction to the injury is surprisingly remarkably similar. However, although in humans the process ends at that time, it continues in fish. They create brand-new cardiomyocytes that may contract, according to Junker.

He says, "We sought to find the signals that originate from other cells and trigger the regeneration. The damaged heart was examined by Junker's team using single-cell genomics to look for cells that are absent from a healthy zebrafish heart.

The researchers found three novel fibroblast kinds that transiently activate. These activated cells, which resemble other fibroblasts in appearance, have the capacity to read a number of extra genes that are involved in the production of proteins, including connective tissue components like collagen 12.

Fibrosis, also known as scarring, is thought to prevent the regeneration of the heart in humans. The fibroblasts do appear to be important to the process once they are activated. It became clear how important they are when Panáková used a genetic ploy to turn off the collagen 12-expressing fibroblasts in the zebrafish. Without regeneration, as a result. Fibroblasts are thought to be the source of the repair signals because, according to Junker, "they form right at the site of injury."

Using the LINNAEUS method, which Junker's group invented in 2018, his team created cell lineage trees to determine the origin of these activated fibroblasts. Genetic scars that collectively function as a barcode indicating the place of each cell's origin are used by LINNAEUS.

"We use CRISPR-Cas9 genetic shears to make this barcode. Two cells are connected if they have the same barcode sequence after injury, according to Junker.

The outer layer of the heart (epicardium) and the inner layer were shown to be two sources of transiently activated fibroblasts by the researchers (endocardium). The epicardium was the only place where collagen 12-producing cells were discovered.

On the study, numerous disciplines collaborated closely.

From the fish tests to the genetic studies to the bioinformatic interpretation of the results, several MDC researchers worked together on this study.

Sara Lelek, a main author of the study and the person in charge of the animal testing, states, "For me, the most fascinating part was to see how well our disciplines complimented each other and how we could verify results from bioinformatics on a living animal." "It was a sizable project that gave us all the chance to add our specialties. I believe this is the reason the study is so thorough and beneficial to many scholars.

As a result of our disparate areas of knowledge, Dr. Bastiaan Spanjaard, who is also a lead author, concurs: "We frequently had to explain our experiments and results to one another. The intricate process of heart regeneration is regulated by a wide range of factors. There was a huge amount of data generated by the tests. Getting the right biological signals out of them was quite difficult.

It's still not clear whether injured hearts in mammals like mice and humans lack the required signals or the capacity to read them. In the event that the signals are absent, medication may one day be created to replicate them. Finding a means to imitate signal interpretation would be more harder, according to Junker.

New blood vessels are also formed with the aid of fibroblasts.

Now, the scientists want to focus more on the genes that the momentarily stimulated fibroblasts read more frequently. They are aware that several of the questioned genes play a crucial role in the release of proteins into the environment. And among them may be elements that also have an impact on cardiomyocytes. Additionally, preliminary research suggests that active fibroblasts aid in the formation of new blood arteries that feed the heart with oxygen in addition to helping the heart regenerate.

By MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE IN THE HELMHOLTZ ASSOCIATION 

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