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Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160675 | GEO | 2020/12/16

REPOSITORIES: GEO

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Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [bulk RNA]

Project description:Purpose: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. Methods: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells. Results: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airways, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells. Conclusions: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.

2020-12-16 | GSE160674 | GEO

Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [single-cell RNA-seq]

2020-12-16 | GSE160673 | GEO

Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia

Project description:Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia

| PRJNA673903 | ENA

Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [bulk RNA]

Project description:Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [bulk RNA]

| PRJNA673906 | ENA

Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [single-cell RNA-seq]

Project description:Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia [single-cell RNA-seq]

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Long intergenic non-coding RNA linc-SUMF1-2 mediates CFTR-associated transcriptional regulation in human airway epithelia

Project description:This SuperSeries is composed of the SubSeries listed below.

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CF vs CFTR-corrected hiPSC-airway at ALI

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-02 | GSE203009 | GEO

CFTR-rich ionocytes mediate chloride absorption across airway epithelia.

Project description:The volume and composition of a thin layer of liquid covering the airway surface defend the lung from inhaled pathogens and debris. Airway epithelia secrete Cl- into the airway surface liquid through cystic fibrosis transmembrane conductance regulator (CFTR) channels, thereby increasing the volume of airway surface liquid. The discovery that pulmonary ionocytes contain high levels of CFTR led us to predict that ionocytes drive secretion. However, we found the opposite. Elevating ionocyte abundance increased liquid absorption, whereas reducing ionocyte abundance increased secretion. In contrast to other airway epithelial cells, ionocytes contained barttin/Cl- channels in their basolateral membrane. Disrupting barttin/Cl- channel function impaired liquid absorption, and overexpressing barttin/Cl- channels increased absorption. Together, apical CFTR and basolateral barttin/Cl- channels provide an electrically conductive pathway for Cl- flow through ionocytes, and the transepithelial voltage generated by apical Na+ channels drives absorption. These findings indicate that ionocytes mediate liquid absorption, and secretory cells mediate liquid secretion. Segregating these counteracting activities to distinct cell types enables epithelia to precisely control the airway surface. Moreover, the divergent role of CFTR in ionocytes and secretory cells suggests that cystic fibrosis disrupts both liquid secretion and absorption.

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Chronic β2AR stimulation limits CFTR activation in human airway epithelia.

Project description:Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor-G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist-induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.

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Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-08-30 | E-GEOD-43710 | biostudies-arrayexpress