John Hopkins Medicine researchers produced new evidence from mouse experiments that show that manipulating certain nerve cells or the genes that control them might trigger the formation of new heart muscle cells and restore heart function.
Human heart muscle cells cease to multiply after birth, making any heart injury later in life permanent, reducing function and leading to heart failure.
The results of the study were published in Science Advances to shed new light on how some neurons regulate the number of heart muscle cells.
Nerve cells regulate heart function
Nerve cells are known to regulate heart function but their role and impact during heart development and their effect on muscle cell growth are 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,” said 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.
The research team created a genetically modified mouse model by blocking sympathetic heart neurons in developing mouse embryos and analysed the drivers of heart muscle cell proliferation through the first two weeks of life after birth.
The re-growth of heart muscle cells
The researchers found a significant decrease in the activity of a pair of genes – the period 1 and 2 genes – already known to control the circadian cycle. They discovered that by removing the two circadian genes in mouse embryos, an up to 10% increase in neonatal heart size and the number of cardiomyocytes, or heart muscle cells was found. This suggests 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 that 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,” said 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 muscles cells, and Tampakakis said that 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,” said Chulan Kwon, PhD, 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 also commented that 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.
