When it comes to regeneration, humans are really too weak...

In superhero movies, regeneration is a powerful skill. No matter what kind of damage you take, you can be fully revived and continue fighting. Like the mean Deadpool, you can grow back your broken limbs, your heart and lungs.

Broken arms and legs can continue to grow back｜Giphy

Ordinary people certainly have some regenerative abilities. For example, even if a healthy person donates 2/3 of his liver, the remaining 1/3 can regenerate within a few months and return to its normal size.

But unfortunately, the heart, which is so vital to humans, cannot regenerate.

Our heart is made up of cardiomyocytes. These cells keep the heart beating. Once they are damaged, the heart function will be permanently damaged, and in severe cases, it may even lead to death. Currently, cardiovascular disease is the leading cause of death in the world; in my country, about 330 million people are troubled by cardiovascular disease.

The heart has no regenerative ability. If it can be regenerated, many lives can be saved｜Giphy

If we could give the heart the ability to regenerate, perhaps we could find a way to combat cardiovascular disease.

In order to uncover the secret of heart regeneration, American biologist Kenneth Poss and his team found sentinels in the brain and kidneys that alert heart trauma by studying zebrafish, which have extremely strong regenerative abilities. The damaged heart uses hormones to notify the sentinels in the brain and kidneys, working together with remote organs to regulate heart regeneration and coordinate various physiological changes in this process. This study was published in Nature Cell Biology.

Amazing zebrafish

The phenomenon of organ regeneration is not uncommon in nature. For example, hydra and planarians only need to retain a very small part of their tissue to regrow a complete body. However, zebrafish are the favorite of scientists in studying regenerative ability.

A pair of adult female zebrafish | Azul

First of all, many important organs of zebrafish can regenerate, such as the heart, spinal cord, and fins (corresponding to human limbs). Understanding the regeneration process of these organs can help people better study related diseases and develop treatment plans.

As a vertebrate, zebrafish share many of the same major organs as mammals, so researchers can not only study the regenerative capacity of specific organs, but also understand how different organs communicate and collaborate during the regeneration process.

From an evolutionary perspective, zebrafish and humans are not far apart in similarity, with more than 70% of human genes found in zebrafish. Therefore, studying zebrafish can be a good reference for humans.

Zebrafish are perfect for research because they are similar to humans and have strong regenerative abilities.

How does the heart regenerate?

Adult myocardial cells have no regenerative capacity. When a human heart is damaged, some fibrotic scar tissue will appear, affecting the beating of the heart.

When a person's heart is damaged, the kidneys will also have problems. The kidneys are the "blood filters" in our bodies. They filter out excess water and waste from the blood to form urine, while regulating our body's water and salt balance and controlling blood pressure. When the heart is damaged, it may lead to a series of problems such as insufficient blood flow to the kidneys, increased blood pressure in the renal veins, kidney damage, and even kidney failure.

The zebrafish's heart regeneration ability is much stronger. When its heart is damaged, the remaining cardiomyocytes will begin to reproduce themselves and regrow the lost parts. At the same time, the kidneys can quickly self-regulate and efficiently exchange fluids.

From top to bottom, the zebrafish brain, heart, and kidneys | Reference [1]

When a human heart is damaged, the kidneys can only wait for disaster to strike; but the zebrafish's heart and kidneys are efficiently connected. For them, how do the distant kidneys receive news of heart damage and respond in a timely manner?

Kidney sentinels work together

The researchers in the paper found that when the heart is injured, a sentinel in the kidney, CEN, awakens its response mechanism to actively control fluid balance to cope with the harm caused by heart injury.

Heart: Save me... | Giphy

This sentinel CEN is a DNA sequence, scientifically known as "tissue regeneration enhancer elements" (TREE).

Every cell of an organism contains the same genetic material, DNA. But why do cells with the same genes exhibit different appearances and functions?

Because in different situations, cells can perform different functions by expressing different genes. "Enhancers" are one of the ways cells control gene expression. Enhancers are specific DNA sequences that can control gene expression by binding to proteins.

When the enhancers are open, they can bind to proteins and promote gene expression; when they are closed, the gene expression level will be relatively low. Therefore, tissue regeneration enhancers are some DNA sequences that control the tissue regeneration process, and CEN is one of them.

When CEN opens to welcome guests, it can bind to proteins and promote gene expression｜Giphy

When the heart is injured, CEN opens its arms to welcome the binding of proteins, thereby directly and indirectly controlling the expression of many genes, activating and mobilizing various heart cells, and achieving the purpose of heart regeneration.

However, unlike other tissue regeneration enhancers, the scope of CEN's action is not limited to the heart during heart regeneration - the CEN in the kidneys is also turned on. At the same time, hormones in the body reach the kidneys, activate their receptors, and then bind to the opened CEN, promoting the expression of specific genes in the kidneys, actively regulating fluid balance, and responding to the crisis caused by heart injury.

Without CEN, can zebrafish heart regeneration still be so smooth?

The researchers deleted the CEN sequence from the zebrafish's DNA using gene editing technology. They found that zebrafish without this sentinel can still grow a heart again, but they cannot regulate fluid exchange normally. This may be because there are other "sentinels" in the heart that can control the regeneration of myocardial cells, while in the kidneys, the function of CEN is irreplaceable.

If humans can better utilize their regenerative abilities, human health will be greatly improved｜Giphy

Regeneration is not a battle fought by injured organs alone. Organs that are not directly injured will also respond. If humans can better utilize their regenerative abilities to repair damaged organs, whether they are the heart, kidneys, liver, or hands and feet, they can save countless lives and improve the quality of life of countless people.

References

[1] Sun, F., Ou, J., Shoffner, AR et al. Enhancer selection dictates gene expression responses in remote organs during tissue regeneration. Nat Cell Biol (2022). https://doi.org/10.1038/s41556-022-00906-y

[2]Cardiac regeneration strategies: Staying young at heart https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614484/

[3] How to avoid being “sad” when facing the “number one killer” http://www.news.cn/mrdx/2021-09/30/c_1310219361.htm

[4] What zebrafish cells taught me about regeneration | The amazing regenerative capabilities of zebrafish | Chen-Hui Chen | TEDxTaipeihttps://www.youtube.com/watch?v=PGx3i9_vhZ0

Author:Hazel

Editor: Xiao Towel, You Shiyou

An AI

Ah, our AI can be regenerated by replacing a part.

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