Inflammatory Activity of Epithelial Stem Cell Variants from Cystic Fibrosis Lungs Is Not Resolved by CFTR Modulators.

Autor:	Wang S; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Niroula S; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Hoffman A; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Khorrami M; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Khorrami M; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Yuan F; Department of Anatomy and Cell Biology.; Gene Therapy Center for Cystic Fibrosis and Other Genetic Diseases, and., Gasser GN; Department of Anatomy and Cell Biology.; Gene Therapy Center for Cystic Fibrosis and Other Genetic Diseases, and., Choi S; Department of Anatomy and Cell Biology.; Gene Therapy Center for Cystic Fibrosis and Other Genetic Diseases, and., Liu B; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Li J; AccuraScience, Johnston, Iowa., Metersky ML; Center for Bronchiectasis Care, Pulmonary, Critical Care, and Sleep Medicine, University of Connecticut Health Center, Farmington, Connecticut., Vincent M; Tract Bio, Houston, Texas., Crum CP; Women's and Perinatal Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Boucher RC; Cystic Fibrosis and Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Karmouty-Quintana H; Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas., Huang HJ; Department of Medicine, Houston Methodist Hospital, Houston, Texas; and., Sheshadri A; Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Dickey BF; Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Parekh KR; Department of Anatomy and Cell Biology.; Gene Therapy Center for Cystic Fibrosis and Other Genetic Diseases, and.; Division of Thoracic Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa., Engelhardt JF; Department of Anatomy and Cell Biology.; Gene Therapy Center for Cystic Fibrosis and Other Genetic Diseases, and., McKeon FD; Department of Biology and Biochemistry, University of Houston, Houston, Texas., Xian W; Department of Biology and Biochemistry, University of Houston, Houston, Texas.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2023 Nov 01; Vol. 208 (9), pp. 930-943.
DOI:	10.1164/rccm.202305-0818OC
Abstrakt:	Rationale: CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs. Objectives: To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) lungs, harbor potentially pathogenic stem cell "variants" distinct from the normal p63/Krt5 lung stem cells devoted to alveolar fates, to identify specific variants that might contribute to the inflammatory state of CF lungs, and to assess the impact of CFTR genetic complementation or CFTR modulators on the inflammatory variants identified herein. Methods: Stem cell cloning technology developed to resolve pathogenic stem cell heterogeneity in COPD and idiopathic pulmonary fibrosis lungs was applied to end-stage lungs of patients with CF (three homozygous CFTR:F508D, one CFTR F508D/L1254X; FEV 1 , 14-30%) undergoing therapeutic lung transplantation. Single-cell-derived clones corresponding to the six stem cell clusters resolved by single-cell RNA sequencing of these libraries were assessed by RNA sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants after CFTR gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies. Measurements and Main Results: End-stage CF lungs display a stem cell heterogeneity marked by five predominant variants in addition to the normal lung stem cell, of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophilic inflammation in xenografts in immunodeficient mice. The proinflammatory functions of these three variants were unallayed by genetic or pharmacological restoration of CFTR activity. Conclusions: The emergence of three proinflammatory stem cell variants in CF lungs may contribute to the persistence of lung inflammation in patients with CF with advanced disease undergoing CFTR modulator therapy.
Databáze:	MEDLINE
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