Basal stem cell variant may be therapeutic target in IPF, study finds

Newly found cell variant may be a cause of lung scarring

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Researchers have discovered a variant of the usual basal stem cells found in the lungs that may contribute to scarring, or fibrosis, in people with idiopathic pulmonary fibrosis (IPF) — and which may be a therapeutic target to slow disease progression.

The team found that these basal stem cells, which are small cells found at the base of the lining of the airways, were sensitive to compounds that inhibit cell growth — at least in a lab setting.

“This study breaks new ground by showing lung fibrosis is driven by specific basal stem cell variants that become overly abundant in diseased lungs,” Howard J. Huang, MD, medical director of the Houston Methodist Lung Transplant Center, in Texas, which provided lung tissue for the study, said in a university press release.

“Importantly, these variants are distinct from abnormal variants identified in other chronic lung diseases. These findings suggest therapies selectively targeting these pathogenic [disease-causing] stem cell variants may ameliorate [help to ease] fibrotic lung disease progression,” Huang said.

The new findings were reported in a study, “Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis,” published in the journal Science Translational Medicine.

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Finding a potential therapeutic target for fibrosis

In IPF, or pulmonary fibrosis of unknown cause, scar tissue builds up in the lungs, making it hard for patients to breathe. Over time, such scarring can worsen and cause patients to experience shortness of breath and fatigue.

Basal stem cells help renew and repair the lining of the airways by growing in number and giving rise to other types of cells that have been damaged or lost. Repeated injury to the lungs, however, can result in unwanted changes to these cells.

When this happens, the lining of the airways may not get the revamp it needs. Instead, there’s a higher chance that fibrosis occurs. However, how exactly those unwanted changes result in lung scarring is unclear.

To know more, a team of researchers led by Wa Xian, PhD, and Frank McKeon, PhD, at the University of Houston’s Stem Cell Center, used a technology called single-cell cloning that allows scientists to pick individual basal stem cells from a person’s lungs and then grow them in the lab.

The researchers picked basal stem cells from the lungs of 16 individuals with IPF who had undergone a transplant due to end-stage lung disease, alongside cells from 10 individuals without the disorder. The transplants all had been done at Houston Methodist.

After the cells were grown in the lab, the team “identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic [disease-causing] myofibroblasts,” Xian and McKeon wrote in their report.

This meant that the stem cell variant helped transform lung fibroblasts into myofibroblasts, a type of cell that’s known to drive fibrosis in IPF.

The scientists also found that the stem cell variant was sensitive to pharmacological inhibitors of epidermal growth factor and a mammalian target of rapamycin signaling, which generally promote cell growth.

Transplants of these basal stem cells to mice also were able to recruit myofibroblasts.

The variant “was shown to preexist in low quantities in normal and even fetal lungs,” the researchers wrote.

That suggests that its buildup over time may perhaps contribute to the development of IPF.

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Early work in COPD is basis for new study in IPF

Earlier work by Xian and McKeon showed that people with chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease of the lungs, have three unusual basal stem cell variants. Together, those variants contribute to inflammation, fibrosis, and excessive mucus secretion in the lungs.

“In this study, we applied the same single cell cloning technology used to assess COPD to the lungs of patients with IPF,” Xian said.

“In contrast to the three pathogenic basal cell variants found to dominate the COPD lung, lungs with advanced IPF showed a major basal cell variant,” Xian said.

These findings suggest that the scientists may have uncovered a therapeutic target for IPF.

“Deciphering why these variants come to dominate the lung could aid in our ability to treat” IPF and COPD, McKeon said.

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