Why the adult heart can't regenerate

Electron microscopic images
of fetal (left) and infant (right) rodent heart nuclei.
As heart cells develop, the number of nuclear pores decreases
.
（Credit: Han et al.
, 2022, Developmental Cell, 10.
1016/j.
devcel.
2022.
09.
017）

A new study suggests that quieting communication between heart cells and their environment protects the heart from harmful stress-related signals, such as high blood pressure, but at the cost of preventing heart cells from receiving signals
that promote regeneration.

As mouse heart cells matured, the number of communication pathways called nuclear pores decreased
dramatically.
While this may protect the organ from damaging signals, it may also prevent the regeneration
of adult heart cells.
That's based on new research conducted by scientists at the University of Pittsburgh and the University of Pittsburgh School of Medicine (UPMC
).

The study shows that disrupted communication between heart cells and their surroundings can protect the organ from harmful stress-related signals, such as high blood pressure, but at the cost of preventing heart cells from receiving signals
that promote regeneration.
The study was published today (Oct.
24) in
the journal Developmental Cell.

"This paper explains why adult hearts can't regenerate themselves, but newborn mouse and human hearts can," said senior author Bernhard Kühn, MD, "and these findings represent an important advance in basic understanding of how the heart develops with age and how it evolves to cope with stress
.
" Kühn is Professor of Pediatrics and Director
of the Pediatric Institute for Cardiac Regeneration and Therapy at Pitt Medical School and UPMC Children's Hospital in Pittsburgh.

While the skin and many other tissues of the body retain their ability to repair themselves after injury, the heart is not
.
During human embryonic and fetal development, heart cells undergo cell division to form heart muscle
.
But when heart cells mature in adulthood, they enter a terminal state
where they can no longer divide.

To further understand how and why heart cells change with age, Kühn collaborated with researchers and biomedical imaging experts at Pitt University, Dr.
Yang Liu (associate professor of medicine and bioengineering), and Dr.
Donna Stolz (associate professor of cell biology and pathology and associate director of the Center for Bioimaging) to observe
the nuclear pores.
These perforations in the lipid membrane that surround the cell's DNA regulate the passage
of molecules in and out of the nucleus.

"The nuclear membrane is an impermeable protective layer that protects the nucleus, like asphalt on a highway," said Kühn, who is also a member of
the McGowan Institute for Regenerative Medicine.
"Like a human hole on asphalt, a nuclear pore is a passageway
for information to enter the nucleus through a barrier.
"

Liu used a super-resolution microscope to observe and count the number of
nuclear pores of mouse heart cells or cardiomyocytes.
Throughout development, the number of wells decreased by 63 percent, from an average of 1,856 fetal cells to 1,040 baby cells to just 678 adult cells
.
Stolz confirmed these findings when he used electron microscopy to show that nuclear pore density decreases
during heart cell development.

In previous studies, Kühn and his team demonstrated that a gene called Lamin b2 is important for cardiomyocyte regeneration, which is highly expressed in newborn mice but declines
with age.

In the new study, they found that blocking Lamin b2 expression in mice resulted in a decrease
in the number of nuclear wells.
Mice with fewer nuclear pores have reduced transport of signaling proteins to the nucleus and reduced gene expression, suggesting that reduced communication with age may lead to a decrease
in cardiomyocyte regeneration.

Kühn explains: "These findings show that the number of nuclear pores controls the amount of
information entering the nucleus.
As heart cells mature and nuclear pores decrease, less and less
information reaches the nucleus.
”

In response to stress such as high blood pressure, the nuclei of cardiomyocytes receive signals that modify gene pathways, leading to structural restructuring
of the heart.
This remodeling is a major cause of
heart failure.

The researchers used a mouse model of hypertension to understand how nuclear pores facilitate this remodeling process
.
Mice engineered to express fewer nuclear pores showed less
regulation of gene pathways involved in harmful heart remodeling.
These mice also had better
heart function and survival than mice with more nuclear pores.

Kühn said: "We were surprised by
the extent of the protective effect of reduced nuclear pores in hypertensive mice.
However, fewer channels of communication also limit those beneficial signals
that promote regeneration.
”

References: Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts" by Lu Han, Jocelyn D.
Mich-Basso, Yao Li, Niyatie Ammanamanchi, Jianquan Xu, Anita P.
Bargaje, Honghai Liu, Liwen Wu, Jong-Hyeon Jeong, Jonathan Franks, Donna B.
Stolz, Yijen L.
Wu, Dhivyaa Rajasundaram, Yang Liu and Bernhard Kühn, 24 October 2022, Developmental Cell.