Mouse study suggests manipulating certain nerve cells may help regenerate lost heart muscle


Human heart muscle cells stop multiplying after birth, making any damage to the heart later in life permanent, reducing function and leading to heart failure. Now, however, researchers at Johns Hopkins Medicine say they have new evidence from experiments on mice that manipulating certain nerve cells or the genes that control them could trigger new heart muscle cells to form and restore heart function afterward. heart attack and other heart problems.

Specifically, they say, the results of their study, published on December 1, in Scientists progress, sheds new light on how certain 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 is unclear.

“Our study aimed to examine the role of so-called sympathetic neurons on cardiac development after birth, and what we found is that by manipulating them, there could be enormous potential to regulate the total number of cells. muscles in the heart even after birth, “says Emmanouil Tampakakis, MD, assistant professor of medicine in the Johns Hopkins University School of Medicine and lead author of the study.

The nerve cells that make up the sympathetic nervous system (SNS) control automatic body processes such as digestion, heart rate, and respiration. 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 mouse model genetically modified by blocking sympathetic heart neurons in developing mouse embryos, and analyzed the drivers of cardiac muscle cell proliferation during the first two. weeks of life after birth.

What they found was a significant decrease in the activity of a pair of genes – period 1 and period 2 genes – already known to control the circadian cycle. Remarkably, by suppressing these two circadian genes in mouse embryos, the researchers found an increase in the size of the neonatal heart and an increase in the number of cardiomyocytes, or heart muscle cells, by up to 10%. This suggests that the effect of sympathetic nerves on heart muscle cells is likely mediated by these two circadian or “clock” genes.

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

“Soon after birth, mammals, including humans and mice, stop producing heart muscle cells. And unlike other organs, like the liver, the heart cannot regenerate after being damaged. “, explains Tampakakis. “We have shown that it is possible to manipulate circadian nerves and / or genes, whether through drugs or gene therapy, 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 is over. high initially. By manipulating sympathetic nerves and clock genes – a technique called neuromodulation – researchers believe the heart may be made to respond better to injury.

“Neuromodulation is a fairly new concept in cardiology, and we believe these are the first reports that link clock genes to new growth of heart muscle cells.” says Chulan Kwon, Ph.D., MS, associate professor of medicine and director of the cardiovascular stem cell program at Johns Hopkins University School of Medicine. “Our study, perhaps for the first time, shows what happens if you block the supply of nerves to the heart, and provides new information to develop neuromodulation strategies for cardiac regeneration.”

Tampakakis says his team is working on further experiments to characterize the different groups of neurons that power the heart and demonstrate how these nerves develop and adjust over time and after heart injury.

According to the United States 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, the American Heart Association’s Maryland Stem Cell Research Fund, the WW 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 from the University of Oxford; William Kowalski and Yoh-Suke Mukouyama of the National Institutes of Health.

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


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