$2.7M NIH Grant Supports Work Into Stem Cell Role in Lung Inflammation
A $2.7 million grant from the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), has been awarded to two stem cell researchers at the University of Houston investigating an alternative cause of chronic lung inflammation in people with cystic fibrosis (CF).
The project, led by Frank McKeon, PhD, and Wa Xian, PhD, both with the university’s Department of Biology and Biochemistry and its Stem Cell Center, aims to assess if unusual and pro-inflammatory stem cell subsets, or variants, in CF patients promote such inflammation. The scientists are also working on treatments targeting those variants that may help patients with advanced lung disease, who respond less well to current disease modulator therapies.
Previous work by this team found stem cell variants that contribute to inflammation, tissue scarring, and excessive mucus secretion in the lungs of people with chronic obstructive pulmonary disease (COPD). These scientists believe the same occurs in CF.
“Given the known pathological similarities between COPD and cystic fibrosis, we asked whether the cystic fibrosis lung is also dominated by pathogenic [disease-causing] stem cells,” Xian said in a university press release.
CF, caused by mutations in the CFTR gene, is characterized by the accumulation of abnormally sticky and thick mucus in the lungs, and in organs like the pancreas, liver, and intestines. In the lungs particularly, the mucus has been thought to trap insults like bacteria and cause damaging infections that lead to inflammation.
The two researchers, however, note that recent studies suggest this may not be the case.
“That raised the possibility that inflammation, and perhaps other pathogenic features of CF, are maintained by elements that emerge in the disease that are entirely independent of CFTR activity,” McKeon said.
In their COPD work, the team identified three specific clusters of stem cells in the lungs of these patients that, when injected in mice, promoted the development of cells involved in inflammation, fibrosis (scarring), and the excessive mucus production.
They then generated stem cell libraries using lung tissue collected from four CF patients and discovered the presence of not only the three subsets seen in COPD, but also two other pro-inflammatory subsets.
These harmful stem cell variants may be associated with CF progression, the researchers suggest, in ways that are possibly independent of the gene’s activity. To advance their research, the scientists intend to use CRISPR-Cas9, a genome editing technique, and xenograft (transplant) mouse models.
“CRISPR-Cas9 genome editing, coupled with our xenograft models, offers a powerful and feasible means of assessing the hierarchy of factors secreted by these three pro-inflammatory stem cell variants found in the CF lung,” Xian said.
Current studies show that available modulator therapies can be “game-changers” for many with CF, “though their impact on advanced lung disease may be more modest,” McKeon added.
The scientists are working on small molecule combinations that might show an ability to specifically target harmful stem cell variants in the lungs, allowing for better treatment.
“This is a race against time for patients with CF and other chronic lung diseases, and the targets are now clear,” Xian said.
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