Yale Study Reveals the Role a Previously Overlooked Cell Type Plays in IPF Progression

Yale Study Reveals the Role a Previously Overlooked Cell Type Plays in IPF Progression
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Yale, pericytes, IPF

A new study from Yale University has found that cells located along the walls of small blood vessels in the lung, called pericytes, promote the progression of idiopathic pulmonary fibrosis (IPF). The role these cells play in fibrosis previously had not been understood.

The study, “Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung,” was published in the Journal of Clinical Investigation Insight.

IPF is a type of lung disease whose cause is unknown. It is characterized by the presence of scarred and hardened tissue, called fibrotic tissue, in the lungs. Changes in the extracellular matrix, a network of diverse types of molecules that help bind cells together and regulate their function, have been associated with the disease.

Pericytes are cells located at intervals along the walls of capillaries, the smallest blood vessels in the body. These important cells are found in the body’s organs including the lungs, heart, and brain, and have been implicated in the development of tissue fibrosis.

The Yale research team set out to better understand the role these cells play in IPF, an approach that differs from that of other tissue engineers, who study cells in arteries and other larger blood vessels.

“We’re looking at these vessels because when IPF gets pretty bad, those small vessels go away and the tissue dies because there is limited nutrient and oxygen delivery to it,” Anjelica Gonzalez, associate professor of biomedical engineering and the study’s senior author, said in a press release.

To discover exactly what happens to this tissue, the investigators collected lung samples from IPF patients and analyzed the fibrotic lesions. They found that pericytes made up 15 to 21 percent of the lesions. No previous study had reported the presence of pericytes in these lesions, Gonzalez noted.

“Now we see that these blood vessel cells are still alive – they just become dysfunctional, as opposed to being supportive of healthy tissue,” Gonzalez said.

To better understand the mechanisms linking pericytes to the development of fibrosis, researchers engineered a human lung that could mimic the transition from healthy tissue to fibrotic tissue.

Using this lung model, investigators found that the cells were healthy as long as the tissue was soft and pliable. But when they were exposed to circulating factors, including the pro-inflammatory molecule TGF-beta1, the cells deposited proteins that caused tissue stiffness and scarring.

A key factor in the conversion from healthy to fibrotic behavior was a process called mechanosensing, which refers to the cells’ ability to sense physical forces transmitted by the surrounding extracellular matrix or neighboring cells.

Importantly, researchers found that this process could be disrupted with the administration of Boehringer Ingelheim’s IPF medication Ofev (nintedanib). Ofev’s effect on pericytes had not been demonstrated in previous studies.

“Our studies also present a potentially novel mode of action for the antifibrotic agent nintedanib,” the researchers wrote.

The next step will be to try to inhibit or reverse the fibrotic processes. The research team will test several therapies that already have been approved or are in the process of seeking approval, for their potential to revert diseased cells and tissues to a healthier state.

Ultimately, the findings may also contribute to the development of therapies that enable the formation of new vessels, the team said. Furthermore, this approach could also be applied to fibrosis of the skin, heart, and other tissues, Gonzalez added.

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