Stem cell cloning experts unravel cystic fibrosis
Newswise – Two nationally recognized experts in cloning and stem cell science at the University of Houston are taking the first step towards limiting the consequences of chronic inflammation in cystic fibrosis (CF) by identifying the source of this persistent and enigmatic inflammation in CF lungs.
Frank McKeon and Wa Xian of the UH Department of Biology and Biochemistry and Stem Cell Center received a $2.7 million grant from the National Heart, Lung, and Blood Institute to examine pro- inflammation in cystic fibrosis.
Cystic fibrosis is an inherited and progressive disease that causes long-lasting lung infections and limits the ability to breathe. It is caused by a defect in a gene called cystic fibrosis transmembrane conductance regulator (CFTR) and affects more than 30,000 people in the United States. This defect commands the body to produce abnormally sticky, thick mucus that clogs organs, especially the lungs, causing chronic lung disease marked by infections and inflammation.
While it has always been assumed that inflammation in the CF lung is a normal response to bacterial infections, recent studies have cast doubt on this link and made the source of this inflammation a mystery.
“This raised the possibility that inflammation, and perhaps other pathogenic features of cystic fibrosis, are maintained by elements that emerge in the disease that are entirely independent of CFTR activity,” McKeon said. .
Interestingly, the same situation can occur in chronic obstructive pulmonary disease (COPD), where inflammation and disease progression continue despite smoking cessation. In COPD, recent studies reported by the Xian-McKeon laboratory have shown a strong correlation between the emergence of pro-inflammatory stem cell variants and the disease itself.
Using technology that clones stem cells from normal lungs, the Xian-McKeon lab found that the COPD lung was dominated by three stem cell variants that drive all COPD pathology, including inflammation, fibrosis and mucin hypersecretion.
“Given the known pathological similarities between COPD and cystic fibrosis, we asked if the cystic fibrosis lung is also dominated by pathogenic stem cells,” Xian said. “We generated stem cell libraries from four CF lungs that showed not only the three variants seen in COPD, but also two additional pro-inflammatory variants.”
The team hypothesizes that these cystic fibrosis stem cell variants play a key role in the progression of cystic fibrosis and represent pathogenic elements of this disease triggered by the CFTR gene and yet independent of it.
To identify the main inflammatory drivers in the three variants, McKeon and Xian will use CRISPR-Cas9 gene editing, which allows them to quickly create cellular models.
“CRISPR-Cas9 genome editing, combined with our xenograft models, offers a powerful and feasible way to assess the hierarchy of factors secreted by these three pro-inflammatory stem cell variants found in CF lung,” said Xian.
The Xian-McKeon studies are at the dawn of a new class of CF drugs that restore CFTR activity in these patients.
“Clinical studies suggest that early application of CFTR modulators will be a game-changer for cystic fibrosis, although their impact on advanced lung disease may be more modest,” McKeon noted.
Anticipating the need for companion drugs for advanced CF, the Xian-McKeon lab is developing small molecule combinations that selectively target pathogenic stem cell variants in the CF lung, while sparing normal cells needed for regenerative repair.
“This is a race against time for patients with cystic fibrosis and other chronic lung diseases, and the goals are now clear,” Xian said.