UH experts in cloning and stem cell science take first step toward unraveling cystic fibrosis

Two nationally recognized experts in cloning and stem cell science from the University of Houston are taking the first step to mitigate the effects of chronic inflammation in cystic fibrosis (CF) by identifying the source of this persistent and puzzling inflammation in CF lungs.

Frank McKeon and Wa Xian of the Department of Biology and Biochemistry and the Stem Cell Center at the UH have received a $2.7 million grant from the National Heart, Lung, and Blood Institute to investigate pro-inflammatory stem cell variants in cystic fibrosis.

Cystic fibrosis is a hereditary and progressive disease that causes long-term lung infections and limits the ability to breathe. It is caused by a defect in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) and affects more than 30,000 people in the United States. That defect instructs the body to produce abnormally sticky and thick mucus that clogs organs, especially the lungs, causing chronic lung disease characterized by infections and inflammation.

While inflammation in the CF lung has always been believed to be a normal response to bacterial infections, recent studies have questioned that link and made the cause of this inflammation a mystery.

That raised the possibility that inflammation, and perhaps other pathogenic features of CF, are maintained by elements emerging in the disease that are completely independent of CFTR activity.”

Frank McKeon, Department of Biology and Biochemistry and the Stem Cell Center of UH

Interestingly, the same situation can occur in chronic obstructive pulmonary disease (COPD), where inflammation and disease progression continues despite smoking cessation. In COPD, recent studies from the Xian-McKeon lab 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 cause all the pathology of COPD, including inflammation, fibrosis and mucin hypersecretion.

“Given the known pathological similarities between COPD and cystic fibrosis, we wondered whether the lung with cystic fibrosis is also dominated by pathogenic stem cells,” says Xian. “We generated stem cell libraries from four CF lungs that displayed not only the three variants seen in COPD, but also two additional, pro-inflammatory variants.”

The team hypothesizes that these CF stem cell variants play a key role in the progression of CF and represent pathogenic elements of this disease caused by, yet independent of, the CFTR gene.

To identify the key inflammatory factors in the three variants, McKeon and Xian will use CRISPR-Cas9 gene editing, which will allow them to quickly create cell models.

“CRISPR-Cas9 genome editing, in combination with our xenograft models, provides a powerful and feasible way to assess the hierarchy of factors secreted by these three pro-inflammatory stem cell variants found in the CF lung,” said Xian.

The Xian-McKeon trials are on the cusp of a new class of cystic fibrosis drugs that restore CFTR activity in these patients.

“The clinical studies suggest that the early application of the CFTR modulators will be a breakthrough for CF, although their impact on advanced lung disease may be more modest,” noted McKeon.

The Xian-McKeon lab addresses the need for companion drugs for advanced CF and is developing small molecule combinations that selectively target the pathogenic stem cell variants in the CF lung while sparing the normal cells needed for regenerative repair.

“This is a race against time for patients with CF and other chronic lung diseases, and the goals are now clear,” said Xian.

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