Mouse study suggests manipulation of certain nerve cells can help
regenerate lost heart muscle

Date:
December 2, 2021
Source:
Johns Hopkins Medicine
Summary:
Human heart muscle cells cease to multiply after birth, making any
heart injury later in life a permanent one, reducing function and
leading to heart failure. Now, however, researchers say they have
new evidence from mouse experiments that manipulating certain nerve
cells or the genes that control them might trigger the formation
of new heart muscle cells and restore heart function after heart
attacks and other cardiac disorders.



FULL STORY ========================================================================== Human heart muscle cells cease to multiply after birth, making any heart
injury later in life a permanent one, reducing function and leading to
heart failure.

Now, however, Johns Hopkins Medicine researchers say they have new
evidence from mouse experiments that manipulating certain nerve cells
or the genes that control them might trigger the formation of new heart
muscle cells and restore heart function after heart attacks and other
cardiac disorders.


==========================================================================
More specifically, they say, results of their study, published Dec. 1,
in Science Advances, sheds new light on how some neurons regulate the
number of heart muscle cells.

Nerve cells have long been known to regulate heart function, but their
role and impact during heart development and their effect on muscle cell
growth has been unclear.

"Our study sought to examine the role of so-called sympathetic neurons on
heart development after birth, and what we found is that by manipulating
them, there could be tremendous potential for regulating the total
number of muscle cells in the heart even after birth," says Emmanouil Tampakakis, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine, and the lead author of the study.

The nerve cells that make up the sympathetic nervous system (SNS)
control automatic processes in the body such as digestion, heart rate
and respiration.

The SNS is typically associated with "fight-or-flight" responses, the
body's general response to alarming, stressful or threatening situations.

For the new study, the research team created a genetically modified mouse
model by blocking sympathetic heart neurons in developing mouse embryos,
and analyzed the drivers of heart muscle cell proliferation through the
first two weeks of life after birth.



==========================================================================
What they found was a significant decrease in the activity of a pair of
genes - - the period 1 and period 2 genes -- already known to control
the circadian cycle. Remarkably, removing those two circadian genes in
mouse embryos, the researchers saw increased neonatal heart size and an increase in the number of cardiomyocytes, or heart muscle cells, by up to
10%. This suggested that the effect of sympathetic nerves on heart muscle
cells is likely mediated through these two circadian or "clock" genes.

Clock genes are components of the circadian rhythm pattern that in mammals regulates bodily functions on a more-or-less 24-hour cycle aligned with
hours of daylight and darkness.

"Shortly after birth, mammals, including people and mice, stop producing
heart muscle cells. And unlike other organs, like the liver, the heart
can't regenerate after it's damaged," says Tampakakis. "We've shown
that it may be possible to manipulate nerves and/or circadian genes,
either through drugs or gene therapies, to increase the number of heart
cells after birth." People who survive a heart attack can lose up to
a billion heart muscle cells, and Tampakakis says there is scientific
evidence that hearts tend to recover faster after an attack when the
total number of cells to begin with is higher.

By manipulating sympathetic nerves and clock genes -- a technique called neuromodulation -- researchers believe the heart could be made to respond
to injury much better.

"Neuromodulation is a pretty new concept in cardiology, and we believe
these are the first reports that associate clock genes with new growth of
heart muscle cells." says Chulan Kwon, Ph.D., M.S., associate professor
of medicine and director of the Cardiovascular Stem Cell Program at the
Johns Hopkins University School of Medicine. "Our study, maybe for the
first time, shows what's happening if you block the supply of nerves
to the heart, and provides new insights for developing neuromodulation strategies for cardiac regeneration." Tampakakis says his team is
working on further experiments to characterize the different groups of
neurons that supply the heart and demonstrate how those nerves develop
and adjust over time and after heart injury.



========================================================================== According to the U.S. Centers for Disease Control and Prevention, cardiovascular disease remains the most common cause of death in the
country causing one in four deaths.

This work was supported by the National Institutes of Health, American
Heart Association Maryland Stem Cell Research Fund, W.W. Smith Charitable Trust, the Magic that Matters Fund and The JHU Mirowski Discovery Award.

Other scientists who conducted the research include Harshi Gangrade,
Stephanie Glavaris, Myo Htet, Sean Murphy, Brian Leei Lin, Ting Liu,
Amir Saberi, Matthew Miyamoto, of Johns Hopkins Medicine; Gabsang Lee
of Johns Hopkins University School of Medicine; Liliana Minichiello
of Oxford University; William Kowalski and Yoh-Suke Mukouyama of the
National Institutes of Health.

None of the authors have disclosures or conflicts of interest in the
study to report.

========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Emmanouil Tampakakis, Harshi Gangrade, Stephanie Glavaris, Myo
Htet, Sean
Murphy, Brian Leei Lin, Ting Liu, Amir Saberi, Matthew Miyamoto,
William Kowalski, Yoh-Suke Mukouyama, Gabsang Lee, Liliana
Minichiello, Chulan Kwon. Heart neurons use clock genes to control
myocyte proliferation.

Science Advances, 2021; 7 (49) DOI: 10.1126/sciadv.abh4181 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211202092953.htm

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