After the central nervous system, heart muscle is one of the least capable tissues in the body when it comes to regeneration following injury. This is one of the contributing factors to the downward spiral of heart health in later life, particularly the cell death and scarring that occurs following the ischemia of a heart attack. Researchers here suggest that this lack of regenerative capacity is the rest of an adaptation in the nuclear membrane that protects heart cells from other damaging circumstances by reducing the number of pathways that allow signal molecules to pass into the cell nucleus. That is protective against harmful signals, but also interferes in the signaling necessary for regeneration.
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, researchers looked 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.
Using super-resolution microscopy, researchers 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 via electron microscopy to show that nuclear pore density decreased across heart cell development.
Previously, researchers 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, researchers found 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.
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.
These findings demonstrate that the number of nuclear pores controls information flux into the nucleus. As heart cells mature and the nuclear pores decrease, less information is getting to the nucleus. A reduced number of communication pathways protects the organ from damaging signals, such as those resulting from high blood pressure, but may also prevent adult heart cells from regenerating.
Link: https://www.upmc.com...ells-regenerate
View the full article at FightAging
