You may be ignoring the news to curb stress and anxiety, but you do so at your own peril. A new study from the University of Pittsburgh (Pitt) and University of Pittsburgh School of Medicine (UPMC) reveals a similar situation in muscle cells of the heart.

Bernhard Kühn, M.D., professor of pediatrics and director of the Pediatric Institute for Heart Regeneration and Therapeutics at the University of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh [UPMC]

Nuclear pore complexes form nanometer scale doorways into the inner sanctum of the cell and are essential for the transport of biomolecules. The new study conducted on mice shows, as heart muscle cells mature, the number of nuclear pores decrease substantially. This reduces the import of proteins into the nucleus which in turn reduces adverse remodeling in response to stress and improves heart function. Stressors such as high blood pressure modify genetic pathways in heart muscle cells that lead to structural remodeling, which is a major cause of heart failure. Unfortunately, this ingenious protective strategy backfires when it comes to regeneration.

Senior author of the study Bernhard Kühn, MD, professor of pediatrics, director of the Pediatric Institute for Heart Regeneration and Therapeutics at UPMC, and a member of the McGowan Institute for Regenerative Medicine, said, “We were surprised at the magnitude of the protective effect of having fewer nuclear pores in mice with high blood pressure. However, having fewer communication pathways also limits beneficial signals such as those that promote regeneration.”

Nuclear Pores
Electron microscopy images of fetal (left) and infant (right) rodent heart cell nuclei. As heart cells develop, the number of nuclear pores decreases [Han et al., 2022, Developmental Cell]

The scientists demonstrate that while closing doors to damaging signals from the environment might protect heart muscles from stress-induced damage, it could also prevent adult heart cells from renewing by blocking signals that promote regeneration.

Yang Liu, PhD, associate professor of medicine and bioengineering at the University of Pittsburgh [UPMC]

Cells in skin, bones, and other human tissues retain the ability to divide and repair themselves after injury, even into old age. But heart muscle cells don’t divide once they attain adulthood. Kühn collaborated with Pitt scientists, Yang Liu, PhD, associate professor of medicine and bioengineering, and Donna Stolz, PhD, associate professor of cell biology and pathology and associate director of the Center for Biologic Imaging, to analyze nuclear pores in his quest to understand why adult heart cells fail to regenerate.

“The nuclear envelope is an impermeable layer that protects the nucleus like asphalt on a highway,” said Kühn. “Like manholes in this asphalt, nuclear pores are pathways that allow information to get through the barrier and into the nucleus.”

Donna Stolz, PhD, associate professor of cell biology and pathology and associate director of the Center for Biologic Imaging at the University of Pittsburgh

Super-resolution microscopy enabled Liu to count the number of nuclear pores in fetal and adult mouse heart cells. She found the number of pores decreased by 63% across development. Stolz used electron microscopy to validate that nuclear pore density decreased across heart cell development.

Earlier work by Kühn’s team had shown Lamin b2, a gene highly expressed in newborn mice and crucial for the regeneration of heart muscle cells, declines with age. In the new study, the team shows, suppressing Lamin b2 in mice decreased the number of nuclear pores. Transport of signaling proteins to the nucleus and gene expression diminished in these mice, indicating reduced communication with age may drive a decrease of regenerative capacity in heart muscle cells.

“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.”

The investigators also observed, a mouse model of high blood pressure engineered to express fewer nuclear pores showed decreased modulation of genetic pathways involved in harmful heart muscle remodeling. These mice had better heart function and longer lifespans than control mice.

“This paper provides an explanation for why adult hearts do not regenerate themselves, but newborn mice and human hearts do,” said Kühn. “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.”

A limitation of the study is posed by the lack of a technique to quantify ploidy—the number of sets of chromosomes in a cell—and the number of nuclear pores in the same nuclei. Kühn’s earlier study had shown suppressing Lamin b2 expression increases the formation of polyploid nuclei. Whether polyploidy affects the number of nuclear pores remains to be discovered.