The regeneration of the heart is one of the greatest current challenges of scientific research. Unlike other animals, such as salamanders or zebrafish, humans are unable to regenerate their tissues and organs, but scientists do not know the causes. Elly Tanaka, from the Institute of Molecular Pathology in Vienna (Austria), spoke about this during the CNIC Conference 2022, a scientific meeting in which the latest advances in the understanding of cardiac repair mechanisms in organisms that they regenerate naturally and how they can be stimulated in mammals that do not regenerate. Tanaka has been fascinated for years with the highly regenerative ability of Ambystoma mexicanum, commonly called axolotl. «All species of salamander that have been studied appear to be capable of regenerating their limbs.», he assures.

Are we humans that different from salamanders?

I have always been fascinated by salamanders for their ability to regenerate. Salamanders are extraordinary creatures. If they lose a finger, it grows back. In addition, if a piece of the heart or spinal cord is cut off, they are also capable of regenerating them. My laboratory, specifically, works with axolotls, salamanders that live in the lakes of Mexico City. At the beginning, we saw that they were capable of regenerating their limbs, but recently, we have observed that they also regenerate their internal organs, such as the heart and brain. In our latest work we have analyzed the sequence of events that occur in brain cells and we have been able to see how the brain regenerates.

How can this information be used to advance the regeneration of tissues and organs in humans?

The data we have obtained is really important for the research that is being done on organ regeneration in humans. Recently we have seen that the stem cells of the axolotl brain are similar to the stem cells that we can find in the brains of mammals. In addition, we have identified special genes that are activated in these axolotl brain stem cells. In the future we are going to analyze whether we can activate these genes in mice, and why not in humans, and inactivate genes that are not related to regeneration. Humans and mice have these genes; now we have to see which genes are active or not in humans.

While the skin and many other tissues in the human body retain the ability to repair themselves after injury, the same is not true of the heart. What can be learned from these other tissues?

It’s hard to have an answer for this. We think it’s possible that humans have a greater number of cells that block regeneration than there are in axolotls. The thing is, we don’t know why. One hypothesis is that the axolotl and other salamanders have a different regeneration mechanism than humans, while in mammals this mechanism is more related to survival. One way would be to identify and characterize these cells involved in regeneration and try to modify them.

Cell therapy and gene therapy are two approaches that have been tried for some time to regenerate the heart without results. Why?

In the 1970s, the then US President Nixon [Richard] declared war on cancer in the US and now, more than 50 years later, we have highly effective cancer therapies. I hope that in the next 10 or 20 years we will have something similar in cardiac regeneration that will revolutionize this field as, for example, cancer immunotherapy has. Of course, the immune system is very relevant and we are seeing that, in some way, the cells of the immune system help regeneration in animals that are capable of regenerating, while in mammals these cells do not seem to help. youWe need to understand this balance between immune cells.

More than 50 years ago, salamanders were the first animal in which cardiac muscle cells were shown to have the ability to regenerate the heart.

Do you think that salamanders can offer new perspectives to improve the treatment of injuries in humans?

We hope it is. There are some laboratories studying in the field of the spinal cord. My team is working with mammalian cells to analyze regeneration patterns in culture. I believe that the results that we are obtaining in salamanders are going to be very useful, not only for the regeneration of the spinal cord.

Is the salamander the most important animal in the field of regeneration?

I am fascinated by these amphibians. For example, in the field of heart regeneration, more than 50 years ago salamanders were the first animal in which cardiac muscle cells were shown to have the ability to regenerate the heart. For years researchers have searched for cardiac stem cells, but the results have been very confusing. Recently, in the last 10 to 15 years, we have been able to understand that the muscle cells of mice and humans regenerate in a similar way to that of salamanders and, now, certain factors have been identified that allow these cells to proliferate. And all these ideas come from studies in salamanders. What we are learning in the salamander is key information to understand what can happen in humans. It is a model that tells us which is the right path.

It is difficult to always make predictions, but we are on the right track

The RegGeneMems project, financed with European funds, ends in 2023. What results can it bring?

If we want to advance tissue bioengineering in humans in the future we have to try to regenerate a larger limb; that is, when we regenerate members in the embryo, they are very small, but if there is an amputation, we have to do it with something bigger. This project tries to understand how an adult salamander is capable of regenerating one of its members. We know that it uses the same components as an embryo and the cells need to communicate with each other. The difference is that, in the embryo, the distance between the cells is smaller; however, in the case of adults, the distance between these cells is much greater. What we’ve seen is that somehow, in larger animals, the factors that these cells use to communicate are able to communicate over greater distances. Animals can use these factors, even at greater distances. And that’s what we want to find out. How does this occur? The idea is to understand how these factors are able to communicate over long distances..

But humans have that ability to regenerate in the first days of life. Do we then lose that capacity for communication between cells and factors??

Yes, distance is certainly a problem that makes communication difficult, but there are other drawbacks. For example, in mammals, cells do not have the capacity to activate these communication molecules because after those first moments of life, not needing them, these factors are deactivated. Thus, while axolotls can reactivate them, this is not the case in mammals.

ESo, will it be possible to regenerate the heart after a heart attack in the future?

It is difficult to always make predictions, but we are on the right track.

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