Journal article
Transgenic ferret models define pulmonary ionocyte diversity and function
Nature (London), Vol.621(7980), pp.857-867
09/28/2023
DOI: 10.1038/s41586-023-06549-9
PMCID: PMC10533402
PMID: 37730992
Abstract
Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity—leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl− and HCO3−. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.
Details
- Title: Subtitle
- Transgenic ferret models define pulmonary ionocyte diversity and function
- Creators
- Vamsidhar Akurathi - University of IowaFeng Yuan - University of IowaDavid W Dick - University of IowaGrace N Gasser - University of IowaThaddeus J Wadas - University of IowaEvan Lemire - Harvard UniversityNam Soo Joo - Stanford UniversityDaniel T Montoro - Broad InstituteJeffrey J Wine - Stanford UniversityKarthik Jagadeesh - Broad InstituteSusan Birket - University of Alabama at BirminghamYan Zhang - University of IowaCourtney M Fernandez - University of Alabama at BirminghamYifan Duan - Harvard UniversityHui Min Leung - Massachusetts General HospitalVitaly Ievlev - University of IowaGuillermo J Tearney - Massachusetts General HospitalKristen L Wells - University of Colorado Anschutz Medical CampusAlan S VerkmanPavana G Rotti - Massachusetts Institute of TechnologyPeter M HaggieWeam Shahin - University of IowaKathleen Scott - Iowa Department of Natural ResourcesMichael Winter - University of IowaDouglas Bartels - University of IowaBradley H Rosen - Indiana UniversityDavid K Meyerholz - University of IowaIdil Evans - University of IowaSteven M Rowe - University of Alabama at BirminghamQian Cai - University of IowaXiaoming Liu - University of IowaMiao Yu - University of IowaZiying Yan - University of IowaSusan A Walsh - University of IowaAdam L Haber - Harvard UniversityMichael R Acevedo - University of IowaXingshen Sun - University of IowaDarpan N Pandya - University of IowaJohn F Engelhardt - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.621(7980), pp.857-867
- DOI
- 10.1038/s41586-023-06549-9
- PMID
- 37730992
- PMCID
- PMC10533402
- NLM abbreviation
- Nature
- eISSN
- 1476-4687
- Language
- English
- Electronic publication date
- 09/20/2023
- Date published
- 09/28/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984466699202771
Metrics
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