Zebrafish can regenerate an entire heart

By copying the tricks of these fish, researchers hope to be able to completely cure a heart patient in the long term.

Cardiovascular diseases are one of the most common causes of death in the world. It is estimated that such diseases claim the lives of as many as 18 million people every year. Heart attacks are especially common. Scientists are therefore diligently looking for ways to restore the heart after a stroke. And thanks to the zebrafish, we are now one step closer.

Heart attack
Unfortunately, the human heart is not well able to repair itself after damage, such as a heart attack. “A heart attack is caused when a blood vessel in the heart closes, so that part of the heart muscle does not receive blood and dies,” explains Dutch researcher Jeroen Bakkers, affiliated with the Hubrecht Institute, in conversation with Scientias.nl out. “The millions of heart muscle cells that are lost as a result are not replaced by new heart muscle cells, but by a scar. This scar causes the heart to work less well. The heart muscle cells that remain try to compensate by working harder. The stress of that hard work can eventually result in heart failure.” Although there are treatments that combat symptoms, it is currently impossible to replace the lost tissue with functional, mature cells that can fully repair a heart.

Unlike humans, some animals, including zebrafish and salamander, can completely regenerate their hearts. That’s because surviving heart muscle cells can divide, creating new cells. In this way, lost heart muscle cells are replaced, so that heart function is fully restored within 90 days. And that is almost envious. Because why they do – and we don’t? “There are different theories,” says Bakkers. “One of them is that it has to do with the difference in body temperature. Fish and salamanders are cold-blooded while mammals are warm-blooded. To keep the body temperature at 37 degrees, a lot of energy and oxygen is needed. This increased need for oxygen may have led to changes in blood circulation, such as a more powerful heart muscle and higher blood pressure. And we think this has come at the expense of its ability to regenerate the heart.”

Heart regeneration under the microscope
In the new study, Bakkers and his colleagues closely scrutinized the zebrafish. Because what exactly ensures that these fish can fully repair their heart after damage? Previous studies have discovered factors that stimulate the division of heart muscle cells. But what happens to the newly formed heart muscle cells afterwards was still a mystery. In short, until recently it was unclear how these cells stop dividing and then mature so that they contribute to normal heart function.

To study the maturation of the new tissue in detail, the researchers developed a technique in which they cultured thick slices of damaged zebrafish hearts outside the body. This enabled them to study the dynamics of calcium in the heart muscle cells. The movement of calcium in and out of cardiac muscle cells is important for heart contraction – and is therefore an important indicator of their maturation. After a thorough analysis, the researchers discovered that the rate at which calcium flows in and out of the heart muscle cell changes after division. “In order to be able to divide, the heart muscle cells change and acquire other (embryonic) properties,” Bakkers explains.

So far nothing new though. “This has been known for some time,” Bakkers continues. “But what we didn’t know yet was how this cell division stops, so that not too many heart muscle cells are produced. It was also still unclear how these new heart muscle cells regain mature properties.” But thanks to the study, Bakkers now has a strong suspicion. “Leucine-rich repeat-containing protein 10 (or LRRC10 for short) plays an important role in this,” he says. “LRRC10 is a protein that binds to a specific ion channel. Both are located in a certain structure, the so-called ‘cardiac dyad’, which regulates how much and how fast calcium flows in and out of the heart muscle cell. We have discovered that the cardiac dyad and LRRC10 are not only important for regulating the influx and outflow of calcium, but also play an important role in the control of cell division. A lack of LRRC10 causes more cell division in the heart and more immature cells, while overexpression actually blocks the division of heart muscle cells. In short, LRRC10 acts as a switch between cell division and maturation during cardiac regeneration.”

It means that LRRC10 is very important for the cell division and maturation of cardiomyocytes in the zebrafish heart. An interesting new insight. But to what extent can this be translated to mammals, such as humans? To study this, the researchers expressed LRRC10 in cultured mouse and human heart muscle cells. The findings are promising. Because LRRC10 changed calcium metabolism, influenced cell division and promoted cell maturation in a similar way to what the team had seen in zebrafish hearts. “We discovered that LRRC10 stimulates maturation not only in zebrafish, but also in human cardiomyocytes,” says Bakkers.

Repairing the damaged heart
This indicates that LRRC10 could potentially be used to repair damaged human hearts. “After a heart attack, for example, the damaged heart could be injected with heart muscle cells grown in the laboratory,” Bakkers suggests. “One of the problems encountered with cultured cardiomyocytes is that they are immature, so they do not integrate properly in the heart – resulting in fatal arrhythmias. More research is needed to determine exactly how mature cultured cardiomyocytes are after treatment with LRRC10, but it is possible that an increase in maturation promotes the integration of transplanted cells.”

Although there is still a long way to go, the findings from the study may contribute to the development of new treatments for cardiovascular disease. “We now have a better understanding of exactly how zebrafish regenerate their hearts,” Bakkers summarizes. “We discovered a new mechanism that causes heart muscle cells to stop dividing and to acquire properties of mature, mature heart muscle cells. This mechanism is also present in cultured human cardiomyocytes, allowing these cells to be directed to develop more mature properties. In short, we now have a better understanding of how we can give cultured heart muscle cells a more mature character. And that contributes to a better model for testing medicines.”

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