New research published in Developmental Cell has uncovered a possible explanation for why explain why adult heart cells lack regeneration capacity. As heart cells mature in mice, the number of communication pathways called nuclear pores dramatically decreases. While this might protect the organ from damaging signals, it could also prevent adult heart cells from regenerating, the researchers found.
The study, from University of Pittsburgh and UPMC scientists, 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, MD, professor of paediatrics. “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 foetal 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, Prof Kühn teamed up with fellow Pitt researchers 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 Prof Kühn. “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, the researchers visualised 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 foetal cells to 1040 in infant cells to just 678 in adult cells. These findings were validated with electron microscopy to show that nuclear pore density decreased across heart cell development.
In previous research, Prof 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 signalling 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 Prof 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 remodelling of the heart. This remodelling 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 remodelling process. Mice that were engineered to express fewer nuclear pores showed less modulation of gene pathways involved in harmful cardiac remodelling. 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 Prof Kühn. “However, having fewer communication pathways also limits beneficial signals such as those that promote regeneration.”
Source: University of Pittsburgh
