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Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
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Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators
Shan Wang1, Suchan Niroula1, Ashley Hoffman1
1Department of Biology and Biochemistry, University of Houston, Houston, Texas.
American Journal of Respiratory and Critical Care Medicine
|September 11, 2023
Summary
Cystic fibrosis (CF) lungs harbor proinflammatory stem cell variants that persist despite CFTR modulator therapy. These variants contribute to ongoing lung inflammation in advanced CF disease.
Area of Science:
- Pulmonary Medicine
- Stem Cell Biology
- Genetics
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve lung function but do not fully resolve inflammation.
- Persistent lung inflammation in cystic fibrosis (CF) patients necessitates identifying novel therapeutic targets.
- Understanding stem cell heterogeneity in CF lungs is crucial for managing advanced disease.
Purpose of the Study:
- To investigate stem cell variants in CF lungs and their contribution to inflammation.
- To identify specific stem cell variants driving neutrophilic inflammation in CF.
- To assess the impact of CFTR genetic complementation and modulators on these variants.
Main Methods:
- Applied stem cell cloning and single-cell RNA sequencing to end-stage CF lungs.
- Assessed stem cell clones via RNA sequencing and xenografting in immunodeficient mice.
- Evaluated the effect of CFTR activity restoration on identified variants.
Main Results:
- Identified five predominant stem cell variants in CF lungs beyond normal stem cells.
- Three variants exhibited proinflammatory gene expression and induced neutrophilic inflammation in xenografts.
- Proinflammatory functions of these variants remained unaffected by CFTR genetic or pharmacological restoration.
Conclusions:
- Proinflammatory stem cell variants emerge in CF lungs, contributing to persistent inflammation.
- These variants may represent a therapeutic target for advanced cystic fibrosis.
- Current CFTR modulator therapies do not fully address inflammation driven by these stem cell variants.
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