Journal article
Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lung Is Not Resolved by CFTR Modulators
American journal of respiratory and critical care medicine, Vol.208(9), pp.930-943
11/01/2023
DOI: 10.1164/rccm.202305-0818OC
PMCID: PMC10870857
PMID: 37695863
Abstract
Rationale: "CFTR modulator" drugs restore function to mutant channels in cystic fibrosis (CF) patients and lead to improvements in body-mass index and lung function especially in younger patients. While it is anticipated that early treatment with CFTR modulators will significantly delay the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in modulator-treated CF patients with established lung disease, underscoring the need to identify and ultimately target the source of this inflammation in CF lung. Objectives: To examine the stem cell heterogeneity of CF lung to identify stem cell variants that might underlie the chronic lung inflammation in CF and the impact of CFTR genetic complementation or CFTR modulators on the inflammatory properties of the stem cell variants identified herein. Methods: Stem cell cloning technology was applied to CF lungs. Single cell-derived clones were assessed by RNA-sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants following gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: CF lungs display a stem cell heterogeneity marked by six predominant variants of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophil inflammation in xenografts. The proinflammatory functions of these variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of proinflammatory stem cell variants in CF lung may explain the persistence of lung inflammation in CF patients undergoing CFTR modulator therapy.
Details
- Title: Subtitle
- Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lung Is Not Resolved by CFTR Modulators
- Creators
- Shan Wang - University of HoustonSuchan Niroula - University of HoustonAshley Hoffman - University of HoustonMelika Khorrami - University of HoustonMelina Khorrami - University of HoustonFeng Yuan - University of IowaGrace N Gasser - University of IowaSoon Choi - University of IowaBovey Liu - University of HoustonJustin Li - University of HoustonMark L Metersky - UConn HealthMatthew Vincent - University of HoustonChristopher P Crum - Harvard University PressRichard C Boucher - University of North Carolina at Chapel HillHarry Karmouty-Quintana - The University of Texas Health Science Center at HoustonHoward J Huang - Houston MethodistAjay Sheshadri - The University of Texas MD Anderson Cancer CenterBurton F Dickey - The University of Texas MD Anderson Cancer CenterKalpaj R Parekh - University of IowaJohn F Engelhardt - University of IowaFrank D McKeon - University of HoustonWa Xian - University of Houston
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.208(9), pp.930-943
- DOI
- 10.1164/rccm.202305-0818OC
- PMID
- 37695863
- PMCID
- PMC10870857
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Grant note
- DOI: 10.13039/100004917, name: Cancer Prevention Research Institute of Texas, award: RR15014; name: NIH, award: 1R01 HL136370-01A1; DOI: 10.13039/100004917, name: Department of Defence, Australian Government, award: W81XWH-17-1-0123; DOI: 10.13039/100004917, name: Cystic Fibrosis Foundation, award: BOUCHE15R0
- Language
- English
- Electronic publication date
- 09/11/2023
- Date published
- 11/01/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Cardiothoracic Surgery; Internal Medicine
- Record Identifier
- 9984464481502771
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