As heart cells mature in mice, the number of communication pathways called nuclear pores dramatically decreases, according to new research from University of Pittsburgh and UPMC scientists. While this might protect the organ from damaging signals, it could also prevent adult heart cells from regenerating, the researchers found.
The study, published today in Developmental Cell, suggests that quieting communication between heart cells and their environment protects this organ from harmful signals related to stresses such as high blood pressure, but at the cost of preventing heart cells from receiving signals that promote regeneration.
“This paper provides an explanation for why adult hearts do not regenerate themselves, but newborn mice and human hearts do,” said senior author Bernhard Kühn, M.D., 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. “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.”
While skin and many other tissues of the human body retain the ability to repair themselves after injury, the same isn’t true of the heart. During human embryonic and fetal development, heart cells undergo cell division to form the heart muscle. But as heart cells mature in adulthood, they enter a terminal state in which they can no longer divide.
To understand more about how and why heart cells change with age, Kühn teamed up with fellow 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 Biologic Imaging, to look at nuclear pores. These perforations in the lipid membrane that surround 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.
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