A brand new analysis research means that quieting communication between coronary heart cells and their setting protects this organ from dangerous indicators associated to stresses similar to hypertension, however at the price of stopping coronary heart cells from receiving indicators that promote regeneration.
As coronary heart cells mature in mice, the variety of communication pathways referred to as nuclear pores dramatically decreases. Although this may defend the organ from damaging indicators, it may additionally stop grownup coronary heart cells from regenerating. This is based on new analysis carried out by scientists from the University of Pittsburgh and the University of Pittsburgh School of Medicine (UPMC).
The research means that quieting communication between coronary heart cells and their setting protects this organ from dangerous indicators associated to stresses similar to hypertension, however at the price of stopping coronary heart cells from receiving indicators that promote regeneration. The research was printed immediately (October 24) within the journal Developmental Cell.
“This paper provides an explanation for why adult hearts do not regenerate themselves, but newborn mice and human hearts do,” mentioned senior creator Bernhard Kühn, M.D. “These findings are an important advance in fundamental understanding of how the heart develops with age and how it has evolved to cope with stress.” Kühn is professor of pediatrics and director of the Pediatric Institute for Heart Regeneration and Therapeutics at Pitt School of Medicine and UPMC Children’s Hospital of Pittsburgh
Electron microscopy photos of fetal (left) and toddler (proper) rodent coronary heart cell nuclei. As coronary heart cells develop, the variety of nuclear pores decreases. Credit: Han et al., 2022, Developmental Cell, 10.1016/j.devcel.2022.09.017
While pores and skin and lots of different tissues of the human physique retain the power to restore themselves after harm, the identical isn’t true of the center. During human embryonic and fetal improvement, coronary heart cells bear cell division to type the center muscle. But as coronary heart cells mature in maturity, they enter a terminal state wherein they’ll now not divide.
To perceive extra about how and why coronary heart cells change with age, Kühn teamed up with fellow Pitt researchers and biomedical imaging consultants Yang Liu, Ph.D., affiliate professor of medication and bioengineering, and Donna Stolz, Ph.D., affiliate professor of cell biology and pathology and affiliate director of the Center for Biologic Imaging, to have a look at nuclear pores. These perforations within the lipid membrane that encompass 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 manholes in this asphalt, nuclear pores are pathways that allow information to get 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% across development, from an average of 1,856 in fetal cells to 1,040 in infant cells to just 678 in adult cells. These findings were validated by Stolz who used electron microscopy to show that nuclear pore density decreased across heart cell development.
In previous research, Kühn and his team showed that a gene called Lamin b2, which is highly expressed in newborn mice but declines with age, is important for cardiomyocyte regeneration.
In the new study, they show that blocking expression of Lamin b2 in mice led to a decrease in nuclear pore numbers. Mice with fewer nuclear pores had diminished transport of signaling proteins to the nucleus and decreased gene expression, suggesting that reduced communication with age may drive a decrease in cardiomyocyte regenerative capacity.
“These findings demonstrate that the number of nuclear pores controls information flux into the nucleus,” explained Kühn. “As heart cells mature and the nuclear pores decrease, less information is getting to the nucleus.”
In response to stress such as high blood pressure, a cardiomyocyte’s nucleus receives signals that modify gene pathways, leading to structural remodeling of the heart. This remodeling is a major cause 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 gene pathways involved in harmful cardiac remodeling. These mice also had better heart function and survival than their peers with more nuclear pores.
“We were surprised at the magnitude of the protective effect of having fewer nuclear pores in mice with high blood pressure,” said Kühn. “However, having fewer communication pathways also limits beneficial signals such as those that promote regeneration.”
Reference: “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.
DOI: 10.1016/j.devcel.2022.09.017
Other authors who contributed to this study were Lu Han, Ph.D., Jocelyn D. Mich-Basso, B.S., M.T., Yao Li, Ph.D., Niyatie Ammanamanchi, M.S., Jianquan Xu, Ph.D., Anita P. Bargaje, B.S., Honghai Liu, Ph.D., Liwen Wu, Ph.D., Jong-Hyeon Jeong, Ph.D., Jonathan Franks, M.S., Yijen L. Wu, Ph.D., and Dhivyaa Rajasundaram, Ph.D., all of Pitt or UPMC.
This research was supported by the Richard King Mellon Foundation Institute for Pediatric Research (UPMC Children’s Hospital of Pittsburgh), HeartFest, the National Institutes of Health (R01HL151415, R01 HL151386, R01HL155597, T32HL129949, EB023507 and NS121706-01), the American Heart Association (18CDA34140024), and the U.S. Department of Defense (W81XWH1810070 and W81XWH-22-1-0221), the Clinical and Translational Science Institute at Pitt, and the Aging Institute at Pitt and UPMC.
