During a heart attack, a person’s heart muscle cells (cardiomyocytes) are injured by oxygen deprivation and begin to die off.

After this stage, scar tissue develops, and because we are unable to generate new cardiomyocytes, the heart is unable to pump blood as effectively as it could.

Lower vertebrates, such as zebrafish, have the ability to regenerate organs, including their hearts.

According to Professor Jan Philipp Junker, “We wanted to find out how this little fish does that, and if we could learn from it.” In collaboration with Dr. Daniela Pánkova, the researchers used zebrafish hearts to replicate myocardial infarction injuries.

They monitored the regeneration of the cardiomyocytes using single-cell studies and cell lineage trees. 

The findings of their study were published in the journal “Nature Genetics” today.

Hearts can’t get better on their own

Under a microscope, the researchers began by holding a cold needle to the zebrafish’s one-millimeter-sized heart for a few seconds. Any tissue the needle touches dies.

Similar to people who have experienced a heart attack, this results in an inflammatory reaction, which is followed by fibroblast-produced scarring.

“Surprisingly, the immediate response to the injury is very similar. But,” according to Junker, “while the process in humans stops at that point, it carries on in the fish. They form new cardiomyocytes, which are capable of contracting.”

“We wanted to identify the signals that come from other cells and help drive the regeneration.” 

Junker’s team used single-cell genomics to look for cells in the damaged heart that don’t exist in the heart of a healthy zebrafish.

They found three new kinds of fibroblasts that can become temporarily active.

These activated cells, which are otherwise identical to other fibroblasts, have the ability to read a variety of extra genes that are involved in the formation of proteins, including connective tissue factors like collagen 12.

Fibroblasts transmit the regeneration signal

In humans, fibrosis, also known as scarring, is thought to be a barrier to heart regeneration. But as soon as they reach their momentarily activated state, the fibroblasts seem to be crucial to the process.

When Panáková used a genetic ploy to turn off the collagen 12-expressing fibroblasts in the zebrafish, it became evident just how crucial they are. The result: no regeneration.

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 create this barcode using CRISPR-Cas9 genetic scissors. If, after injury, two cells have the same barcode sequence, it means they’re related,” adds Junker. 

The researchers discovered two sources of momentarily activated fibroblasts: the outer layer of the heart (epicardium) and the inner layer (endocardium) of the heart.

The epicardium was the only place where collagen 12-producing cells were discovered.

Different disciplines collaborated closely on the research

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

Sara Lelek, the main author of the study and the person in charge of animal testing, states, “For me, the most exciting thing was to see how well our disciplines complement each other and how we could verify results from bioinformatics on a living animal.” 

“It was a big project that allowed us all to contribute our expertise. I think that’s why the study is so comprehensive and so useful for many researchers.”

As a result of our disparate areas of knowledge, Dr. Bastiaan Spanjaard, who is also a lead author, agrees: “Heart regeneration is a complex process that’s influenced by many different things. The experiments produced enormous quantities of data. Filtering the correct biological signals out of them was hugely challenging.

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 harder, according to Junker.

Fibroblasts also create blood vessels

Now, the authors 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.

These may include cardiomyocyte-affecting factors.

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.

Image Credit: Getty

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