Revealing the critical role of heart-derived macrophages

CLA researchers have identified for the first time the origin of an immune cell that plays a vital role in the formation of healthy heart valves. The findings could pave the way for new treatments for heart valve disorders, which can be caused by birth defects, aging or diseases.

Their study, led by Dr. Atsushi "Austin" Nakano, badociate professor of molecular biology, cell and development at UCLA and member of the Center for Research on Regenerative Medicine and Stem Cells Eli and Edythe Broad, was published in the journal Developmental Cell. .

Building on previous research from Nakano, which showed that the embryonic cardiac tube produced blood progenitor cells, the new study found that these cells, in turn, generate specialized immune cells, called macrophages. Research has also revealed that these heart-derived macrophages are particularly apt to consume excess tissue, a skill that makes them essential for the formation and maintenance of heart valves.

The human heart has four valves – thin tissue paper membranes that open and close constantly to control blood flow to the heart. When the valves are not working properly, blood circulation in the body is disrupted, putting the heart to the test and can lead to heart failure, stroke or sudden death.

"When the valves are seriously damaged, they can not be repaired. replacement surgery is the only option, "said Nakano." Identifying cells that contribute to the health of the valve could reveal targets for new, less invasive therapies. "

Currently, doctors have two options to replace valves: mechanical valves, which require the long-term use of anticoagulant drugs; and biological valves, made from cardiac tissue of cows, pigs or humans, and which usually need to be replaced every 10 to 15 years.

Because replacement valves often require their own replacement, especially in children, as they tend to lose their replacement multiple times before reaching adulthood, and because of the risks badociated with any surgical procedure altering the heart, Nakano has announced new methods of treating valvular disorders. are urgent.

In a 2013 study of mice, Nakano and his lab colleagues discovered that the heart tube – the shape that the embryonic heart takes before it starts to pump blood – contributes to the production of early blood cells in the body, called blood progenitor cells. Just as stem cells can form any type of cells in the body, blood progenitor cells can create many types of blood and immune cells. But unlike stem cells, blood progenitor cells are not able to renew themselves throughout the life of an organism.

"Since we discovered that the heart tube produces blood progenitor cells, we try to understand why," Nakano said. "The progenitor cells of the blood are generated in greater numbers in other parts of the developing embryo. Having the heart tube produces blood progenitor cells, it's like having a small, little productive plant near a bigger and more productive plant. If both plants produce the same thing, in this case blood progenitor cells, why not have one large plant?

Answering this question was not a simple task, in part because the heart tube changes shape and starts to beat only a few days after its development. And with each heartbeat, the blood and immune cells of the developing embryo as a whole infiltrate into the heart, making it difficult to determine the origin of the blood cells in the heart.

In the new study, which also used mice, the team eliminated other blood and immune cells from the equation by removing a heart tube before starting to pump blood and continue growing in a capsule laboratory. In the absence of blood circulation to contaminate their sample, the team observed that heart-derived blood progenitor cells produced macrophages.

Macrophages ("big eaters" in Greek) reside in the tissues and travel through the body in the blood, seeking and consuming harmful, damaged or unnecessary cells. Previous research had shown the existence of macrophages in the heart valves, but Nakano's team was the first to discover their role: to eat excess cells to make the valves too thin and hyper effective. This process begins in the developing embryo and continues after birth; Macrophages remain in the valves to help keep them in shape throughout the life cycle.

"It was known that macrophages existed in the heart valves, but no one had fixed their arrival and their provenance until we saw them develop in the heart tube," said Nakano.

To test how heart-derived macrophages are essential for valve formation and remodeling, scientists have blocked their production to see if it produced an effect. They discovered that other macrophages in the body – those of circulating blood – were moving towards the heart, but they were not very effective at reshaping the valves. Without the macrophages derived from the heart, the heart valves remained thick and heavy.

"This has shown us that macrophages generated in the heart tube are particularly apt to eat excess tissue," said Nakano. "This makes them indispensable not only for the formation of heart valves, but also for their maintenance throughout life."

Nakano said he hoped the discovery would pave the way for more permanent resolution of heart valve disease, perhaps by reinforcing or inhibiting the activity of heart-derived macrophages to regulate heart valve formation. And, since these macrophages remain in the body throughout people's lives, it may one day be possible to target them to treat valve problems that develop later in life, he said. .

The next step for Nakano's lab will be to determine if the results can be replicated in humans.

This article has been republished from documents provided by the University of California Los Angeles. Note: Content may have changed for length and content. For more information, please contact the cited source.

Reference
The macrophages derived from the endocardial are essential to valve remodeling. Ayako Shigeta et al. Dev. DOI cell: https: //doi.org/10.1016/j.devcel.2019.01.021.