Journal article
Sonic Hedgehog Signaling is Essential for Pulmonary Ionocyte Specification in Human and Ferret Airway Epithelia
American journal of respiratory cell and molecular biology, Vol.69(3), pp.295-309
09/2023
DOI: 10.1165/rcmb.2022-0280OC
PMCID: PMC10503308
PMID: 37141531
Abstract
Pulmonary ionocytes express high levels of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel critical for hydration of the airways and mucociliary clearance. However, the cellular mechanisms that govern ionocyte specification and function remain unclear. We observed that increased abundance of ionocytes in cystic fibrosis (CF) airway epithelium was associated with enhanced expression of Sonic Hedgehog (SHH) effectors. In this study, we evaluated whether the SHH pathway directly impacts ionocyte differentiation and CFTR function in airway epithelia. Pharmacological HPI1-mediated inhibition of SHH signaling component GLI1 significantly impaired human basal cell specification of ionocytes and ciliated cells, but significant enhanced specification of secretory cells. By contrast, activation of the SHH pathway effector SMO with the chemical agonist SAG significantly enhanced ionocyte specification. The abundance of CFTR
BSND
ionocytes under these conditions had a direct relationship with CFTR-mediated currents in differentiated air-liquid interface (ALI) airway cultures. These findings were corroborated in ferret ALI airway cultures generated from basal cells in which the genes encoding the SHH receptor
or its intracellular effector
were genetically ablated using CRISPR/Cas9, causing aberrant activation or suppression of SHH signaling, respectively. These findings demonstrate that SHH signaling is directly involved in airway basal cell specification of CFTR-expressing pulmonary ionocytes and likely responsible for enhanced ionocyte abundance in the CF proximal airways. Pharmacologic approaches to enhance ionocyte and reduce secretory cell specification following
gene editing of basal cells may have utility in the treatment of CF.
Details
- Title: Subtitle
- Sonic Hedgehog Signaling is Essential for Pulmonary Ionocyte Specification in Human and Ferret Airway Epithelia
- Creators
- Qian Cai - Ningxia Medical UniversityMeihui Luo - University of IowaYinghua Tang - University of IowaMiao Yu - Ningxia UniversityFeng Yuan - University of IowaGrace N Gasser - The University of Iowa Roy J and Lucille A Carver College of Medicine, 12243, Anatomy & Cell Biology, Iowa City, Iowa, United StatesXiaoming Liu - University of IowaJohn F Engelhardt
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.69(3), pp.295-309
- DOI
- 10.1165/rcmb.2022-0280OC
- PMID
- 37141531
- PMCID
- PMC10503308
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Grant note
- DOI: 10.13039/100000050, name: National Heart, Lung and Blood Institute, award: R01 HL165404, P01 HL152960, 75N92019C00010; DOI: 10.13039/100000050, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: P30 DK054759; DOI: 10.13039/100000050, name: Cystic Fibrosis Foundation, award: ENGELH20XX2
- Language
- English
- Electronic publication date
- 05/04/2023
- Date published
- 09/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984400756302771
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