Why can't an adult's heart regenerate? The answer is surprising

The liver has the greatest regenerative capacity of any human organ - it can regenerate even after 70% is removed, making living transplantation possible.
However, as the power pump of the human body, the heart cannot regenerate after adulthood. Why is this?
Recently, scientists from the University of Pittsburgh and the University of Pittsburgh Medical Center gave an unexpected answer - actively refusing regeneration in order to protect themselves.

Figure｜Schematic diagram of the human heart (Source: Wikipedia)

They found that as mouse heart cells mature, the number of a type of communication channel called nuclear pores decreases dramatically. While this may protect the organ from harmful signals associated with stress, such as high blood pressure, it comes at the cost of preventing heart cells from receiving signals that promote regeneration, thereby preventing the regeneration of adult heart cells.

The related research paper, titled "Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts", has been published in the scientific journal Developmental Cell.

(Source: Developmental Cell)

“Our study explains why the adult heart cannot regenerate itself, while the hearts of newborn mice and newborns can,” said senior author Bernhard Kühn, associate professor of pediatrics at the University of Pittsburgh School of Medicine. “These findings are an important advance in the basic understanding of how the heart develops as we age and responds to stress.”

The heart is a muscular organ in the animal's circulatory system that pushes blood through blood vessels, providing the body with oxygen and nutrients while also helping the body remove metabolic waste. It is one of the most important organs in the animal body.

Once a human or animal has a heart problem, it will have irreversible effects on the entire body.

Therefore, understanding the developmental mechanisms of the heart is crucial for preventing and treating heart-related diseases.

While human skin and many other tissues retain the ability to repair themselves after injury, the heart cannot.

During human embryonic and fetal development, heart cells divide to form heart muscle, but as they mature in adulthood, they enter a terminal state in which they can no longer divide.

Figure｜Names of various parts of the human heart. (Source: Wikipedia)

To further understand how and why heart cells change with age, the research team looked at the nuclear pores in mice. Nuclear pores are complexes embedded in the nuclear membrane of eukaryotic cells that serve as channels for communication between the nucleus and the cytoplasm.

Like asphalt on a highway, the nuclear membrane is an impermeable layer that protects the nucleus, while the nuclear pores are like manholes on the highway, passages for information to pass through the barrier and into the nucleus.

To do this, the research team used super-resolution microscopy to observe and count the number of nuclear pores in mouse heart cells, or cardiomyocytes.

The results showed that throughout development, the number of nuclear pores decreased by 63%, from an average of 1,856 in fetal cells to an average of 1,040 in infant cells and then to an average of only 678 in adult cells.

Figure | The number of nuclear pores in cardiomyocytes decreases during maturation. (Source: This paper)

In previous studies, the research team verified the importance of a gene called Lamin b2 for cardiomyocyte regeneration.

Expression of this gene is high in newborn mice but decreases with age.

In this study, they found that blocking Lamin b2 expression in mice resulted in a reduction in the number of nuclear pores. Mice with fewer nuclear pores had reduced transport of signaling proteins to the nucleus and decreased gene expression, suggesting that reduced communication with age may contribute to a decline in the regenerative capacity of cardiomyocytes.

"These findings suggest that the number of nuclear pores controls the flux of information into the nucleus. As heart cells mature and the number of nuclear pores decreases, less and less information reaches the nucleus," explains Kühn.

In response to stress, such as high blood pressure, the nuclei of cardiomyocytes receive signals that modify genetic pathways and remodel the heart's structure. This remodeling is a major cause of heart failure.

To this end, the research team sought to understand how nuclear pores promote this remodeling process using a mouse model of hypertension.

They found that

Mice engineered to express fewer nuclear pores had less regulation of gene pathways involved in harmful cardiac remodeling, and these mice also had better heart function and survival than mice with more nuclear pores.

It is for this reason that the adult heart cannot regenerate.

Reference link: https://www.cell.com/developmental-cell/fulltext/S1534-5807(22)00719-5