by As heart cells mature in mice, the number of communication pathways called nuclear pores decreases dramatically, according to new research from scientists at the University of Pittsburgh and UPMC. While this might protect the organ from damaging signals, it might also prevent adult heart cells from regenerating, the researchers found.
The study, published today in development cellsuggests that silencing 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.
“This article provides an explanation for why adult hearts don’t regenerate on their own, but newborn mice and human hearts do,” said lead author Bernhard Kühn, MD, professor of pediatrics and director of the Pediatric Institute for Regeneration. and Heart Therapeutics at Pitt School of Medicine. Medicine and UPMC Children’s Hospital of Pittsburgh. “These findings are an important advance in our fundamental understanding of how the heart develops with age and how it has evolved to cope with stress.”
While the skin and many other tissues in the human body retain the ability to repair themselves after injury, the heart does not. During human embryonic and fetal development, heart cells divide to form heart muscle. But as heart cells mature into adulthood, they enter a terminal state where they can no longer divide.
To understand more about how and why heart cells change with age, Kühn teamed up with other Pitt researchers and biomedical imaging experts Yang Liu, Ph.D., associate professor of medicine and bioengineering, and Donna Stolz, Ph.D., associate professor of cell biology and pathology and associate director of the Center for Biological Imaging, to look at nuclear pores. These perforations in the lipid membrane that surrounds a cell’s DNA regulate the passage of molecules to and from the nucleus.
“The nuclear envelope is an impermeable 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 the sewers in this asphalt, the nuclear pores are pathways that allow information to pass through the barrier and into the nucleus.”
Using super-resolution microscopy, Liu visualized and counted the number of nuclear pores in mouse heart cells, or cardiomyocytes. The number of pores decreased by 63% over development, from an average of 1,856 in fetal cells to 1,040 in infant cells and just 678 in adult cells. These findings were validated by Stolz, who used electron microscopy to show that nuclear pore density decreased throughout heart cell development.
In earlier research, Kühn and his team showed that a gene called lamina b2which is highly expressed in newborn mice but decreases with age, is important for cardiomyocyte regeneration.
In the new study, they show that blocking the expression of lamina b2 in mice it led to a decrease 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 lead to a decline in cardiomyocyte regenerative capacity.
“These findings demonstrate that the number of nuclear pores controls the flow of information into the nucleus,” explained Kühn. “As heart cells mature and nuclear pores shrink, less information reaches the nucleus.”
In response to stress, such as high blood pressure, the nucleus of a cardiomyocyte receives signals that modify genetic pathways, leading to structural remodeling of the heart. This remodeling is one of the main causes of heart failure.
The researchers used a mouse model of high blood pressure to understand how nuclear pores contribute to this remodeling process. Mice that were engineered to express fewer nuclear pores showed less modulation of genetic pathways involved in damaging cardiac remodeling. These mice also had better cardiac function and survival than their peers with more nuclear pores.
“We were surprised by the magnitude of the protective effect of having fewer nuclear pores in mice with high blood pressure,” Kühn said. “However, having fewer communication pathways also limits beneficial signals, such as those that promote regeneration.”
Other authors who contributed to this study were Lu Han, Ph.D., Jocelyn D. Mich-Basso, BS, MT, Yao Li, Ph.D., Niyatie Ammanamanchi, MS, Jianquan Xu, Ph.D., Anita P Bargaje, BS, Honghai Liu, Ph.D., Liwen Wu, Ph.D., Jong-Hyeon Jeong, Ph.D., Jonathan Franks, MS, Yijen L. Wu, Ph.D., and Dhivyaa Rajasundaram, Ph. .D., all from Pitt or UPMC.
This research was supported by the Richard King Mellon Foundation Pediatric Research Institute (UPMC Children’s Hospital of Pittsburgh), HeartFest, the National Institutes of Health (R01HL151415, R01 HL151386, R01HL155597, T32HL129949, EB023507, and NS121706-01), the Association American Heart Association (18CDA34140024) and the US Department of Defense (W81XWH1810070 and W81XWH-22-1-0221), the Pitt Institute for Clinical and Translational Sciences, and the Pitt Institute on Aging and UPMC.
