Inflammatory stem cell activity not eased by CFTR modulators: Study

Therapy shown to help restore more normal mucus production in patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A pair of damaged lungs, breathing with clouds behind them, are pictured.

The lungs of people with cystic fibrosis (CF) harbor stem cells with a distinctive proinflammatory genetic signature, a new study shows.

Data indicate that the proinflammatory genetic profile of these stem cells is not affected by treatment with CFTR modulators, a class of medications that can boost the activity of the defective CFTR protein in people with CF caused by specific mutations.

“These findings raise the possibility that these inflammatory stem cell variants are the source of the persistent inflammation in patients treated with CFTR modulators,” Frank McKeon, PhD, a study author at the University of Houston, said in a university news story.

The study, “Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lung Is Not Resolved by CFTR Modulators,” was published in the American Journal of Respiratory and Critical Care Medicine.

CF is caused by mutations in the gene that provide instructions for making the CFTR protein. When this protein is missing or defective, the body cannot properly regulate the water content of mucus, resulting in the production of thick, sticky mucus that drives most CF symptoms. CFTR modulators, which can increase the CFTR protein’s activity in some patients, have been shown to help restore more normal mucus production.

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CFTR modulators improve lung function

CF is commonly marked by ongoing inflammation in the lungs, which over time leads to progressive damage to lung tissue. While treatment with CFTR modulators can improve lung function, these therapies aren’t as effective for controlling inflammation in the lungs, for reasons that aren’t fully understood.

Stem cells are cells that have the capability to grow into multiple other types of cells. Within the lungs, stem cells help to keep the lining of the lungs healthy, replacing damaged cells.

Here, scientists conducted single-cell analyses where they profiled the gene expression of stem cells in lung samples from people with CF. The team also performed xenograft experiments, where they transplanted human stem cells into mouse lungs to better understand the cells’ biological functions.

The researchers identified distinct genetic profiles of stem cells in the CF lungs. Three of these variants were marked by a proinflammatory profile, with a particular ability to activate inflammatory immune cells called neutrophils.

“We identified five stem cell variants common to lungs of patients with advanced CF, including three that show hyperinflammatory gene expression profiles and drive neutrophilic inflammation upon xenografting to immunodeficient mice,” said Wa Xian, PhD, a study author at the University of Houston.

The researchers further showed that treatment with CFTR modulators did not reduce the inflammatory activity of these stem cells.

“We found that CFTR-modulating drugs did not suppress the proinflammatory activity or gene expression of the three CF variants that drive inflammation,” McKeon said.

The researchers said that these proinflammatory stem cells “may explain the persistence of lung inflammation in CF patients undergoing CFTR modulator therapy.”