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The zebrafish can mend its own heart

Many, but not all, of our body cells are able to constantly renew themselves. In adults however, cells such as nerve or cardiac muscle cells have lost the ability to regenerate. This is why myocardial infarction is so dangerous – damaged cardiac muscle cells do not grow back and scar tissue forms in their place. Prof. Dr. Gilbert Weidinger and an international team of researchers have deciphered a mechanism responsible for the regeneration of the zebrafish heart. This finding could potentially be used for developing drugs to regenerate the human heart.

In Germany, more than 50,000 people suffer a myocardial infarction or heart attack every year. Persistent circulatory problems can lead to potentially life-threatening abnormal heart rhythms and the death of cardiac muscle cells (cardiomyocytes) in the affected area. In patients who survive the acute episode, the cells do not grow back and a scar forms. As a result, the heart is permanently damaged. All mammals lack the ability to regenerate cardiac cells. However, several years ago researchers discovered that the majority of lower animals such as fish and newts have the capacity to renew cardiomyocytes and thus repair heart injuries.

The regenerative capacity of zebrafish is phenomenal

Zebrafish have the outstanding ability to not only regenerate injured fins, but also damaged heart tissue. © Elvira Eberhardt / University of Ulm

Prof. Dr. Gilbert Weidinger and his team of researchers at the Institute for Biochemistry and Molecular Biology at the University of Ulm are exploring the regenerative mechanisms of the zebrafish heart. Zebrafish – Danio rerio – is a popular aquarium fish native to the Ganges river system. The fish are popular model organisms for geneticists and developmental biologists because the relatively big embryos are transparent, which makes it possible to follow developmental processes relatively easily. For the research team from Ulm, the ability of the zebrafish to regenerate damaged organs is of particular interest. It can rapidly regenerate both its heart and severed fins. “This is what makes zebrafish so interesting for us and we want to find out why they have this ability while mammals do not,” says Weidinger summarising his research approach. “To be more specific, we are looking for genes that control the cell division process during regeneration. If we knew the factors and were able to activate them in human beings, we would potentially be able to regenerate human cardiomyocytes. But this is still a pipe dream. We still know far too little about the animals’ regenerative ability. Nevertheless, this is the basic idea behind our research.”

Tomo Seq – high-throughput determination of gene activity

A new sequencing method (Tomo Seq) enables researchers to identify genes that are active in particular regions of the regenerating heart. The left-hand column lists genes that are active in the wound (blue), the middle column indicates active genes at the wound border, and the right-hand column, activated genes in healthy tissue. © Chi-Chung Wu / University of Ulm

The biologists from Ulm and their colleagues from the Hubrecht Institute in the Dutch city of Utrecht, used a completely new RNA sequencing method called Tomo Seq to find out which factors regulate heart regeneration in zebrafish. This efficient new method is used to study the spatial expression pattern of an organism’s entire transcriptome. The technique combines high-throughput gene sequencing with tissue sectioning. RNA is isolated from tissue sections and analysed using next-generation sequencing. This allows the researchers to detect gene activities in the genome as well as in a specific region. Using Tomo Seq, the biologists studied the activity pattern of genes in regenerating zebrafish hearts and obtained a genome-wide atlas of regionally different expression and activity patterns.

The Tomo Seq technique has recently been established by the Dutch researchers for use with zebrafish embryos. “As a world first, we were able to demonstrate in practice that the technique is also suitable for organs,” says the zebrafish researcher from Ulm. “In future, it can also be used to study other organisms.” The novelty of the technique is that it combines different investigational dimensions: “It closes the gap between genome-wide and spatial resolution. Studying genome-wide and regional expression and activity patterns has previously only been possible with a lower throughput,” says Weidinger. “Also the technique is made less complicated by the fact that it is a combination of well-established standard techniques. However, the subsequent bioinformatic analyses are rather complex. The gene expression profiles of the countless individual steps have to be compared with each other, which is a complex and time-consuming process.”

Signalling molecules are reactivated in the wound area

Heart regeneration: BMP signals are necessary for the regeneration of the heart. Their experimental amplification can speed up recovery. The dashed area indicates the injured area that has not yet fully regenerated in the control hearts. The wound is larger (central image) in the heart where BMP signals were blocked, while the heart where BMP signals were amplified, has only minor wounds. © Chi-Chung Wu / University of Ulm

The Tomo Seq technique enabled the scientists to demonstrate that the division of cardiomyocytes is controlled by special proteins. “We already knew that there was a zone between wound and healthy tissue where cardiac cells divide. This does not normally happen in healthy hearts,” says Weidinger. “The new technique allowed us to identify genes that are activated in the region that is crucial for regeneration. In particular, we found that so-called BMPs (bone morphogenetic proteins) are switched on at the wound border.” BMPs have long been known as important signalling molecules that enable cells to communicate with each other. The international team of researchers has now found out that these signalling proteins are reactivated particularly in those wound areas where healthy and injured tissues meet. Using transgenic zebrafish lines in which the BMP signalling pathway was either blocked or activated, the biologists could then specifically influence the regeneration process. It turned out that once the signalling proteins were blocked, no cardiomyocytes were regenerated. On the other hand, the hyperactivation of BMP led to an acceleration in the regeneration rate.

“BMPs are therefore crucial for the division of cardiomyocytes during heart regeneration. However, we were surprised to find that these signalling molecules did not play a role in the division of cardiomyocytes during embryonic development, but only in the regeneration of injury-related cardiac regeneration,” says Weidinger. And yet another astounding finding: BMP signals can be detected in damaged mammalian hearts. "However, they seem to induce the opposite effect. An even larger number of cardiomyocytes dies,” says the biologist from Ulm, adding, “I am sure we can establish a new paradigm. The signal that is switched on when heart injury occurs is the same in fish and mammals. However, the cell response can be completely different. In our search for explanations as to why mammals do not have the capacity to regenerate, we will now have to look into why cardiomyocytes behave so differently.”

Elucidating the function of other candidates

In future, the researchers will have to carry out further experiments on the BMP signalling molecules. They want to find out which BMP molecules are active in mammals and fish and when, and of course, the reason for the differences between fish and humans. In addition, the analysis of the Tomo Seq experiments will come up with many other molecules that might play a role in the regulation of cardiomyocytes and the development of organs in the embryo. The biologists in Weidinger’s laboratory still have a good deal of work to do before they identify the function of these molecules. If one day all the details that favour or inhibit the regeneration of injured cardiomyocytes are known, it will be possible to develop therapies to repair injured human cardiomyocytes as effectively as zebrafish are able to repair theirs.

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