Transgenic ferret models define pulmonary ionocyte diversity and function

Feng Yuan, Grace N. Gasser, Evan Lemire, Daniel T. Montoro, Karthik Jagadeesh, Yan Zhang, Yifan Duan, Vitaly Ievlev, Kristen L. Wells, Pavana G. Rotti, Weam Shahin, Michael Winter, Bradley H. Rosen, Idil Evans, Qian Cai, Miao Yu, Susan A. Walsh, Michael R. Acevedo, Darpan N. Pandya, Vamsidhar Akurathi, David W. Dick, Thaddeus J. Wadas, Nam Soo Joo, Jeffrey J. Wine, Susan Birket, Courtney M. Fernandez, Hui Min Leung, Guillermo J. Tearney, Alan S. Verkman, Peter M. Haggie, Kathleen Scott, Douglas Bartels, David K. Meyerholz, Steven M. Rowe, Xiaoming Liu, Ziying Yan, Adam L. Haber (), Xingshen Sun () and John F. Engelhardt ()
Additional contact information
Feng Yuan: University of Iowa
Grace N. Gasser: University of Iowa
Evan Lemire: Harvard T. H. Chan School of Public Health
Daniel T. Montoro: Broad Institute of MIT and Harvard
Karthik Jagadeesh: Broad Institute of MIT and Harvard
Yan Zhang: University of Iowa
Yifan Duan: Harvard T. H. Chan School of Public Health
Vitaly Ievlev: University of Iowa
Kristen L. Wells: University of Colorado Anschutz Medical Campus
Pavana G. Rotti: Massachusetts Institute of Technology
Weam Shahin: University of Iowa
Michael Winter: University of Iowa
Bradley H. Rosen: Indiana University School of Medicine
Idil Evans: University of Iowa
Qian Cai: University of Iowa
Miao Yu: University of Iowa
Susan A. Walsh: University of Iowa
Michael R. Acevedo: University of Iowa
Darpan N. Pandya: University of Iowa
Vamsidhar Akurathi: University of Iowa
David W. Dick: University of Iowa
Thaddeus J. Wadas: University of Iowa
Nam Soo Joo: Stanford University
Jeffrey J. Wine: Stanford University
Susan Birket: University of Alabama at Birmingham
Courtney M. Fernandez: University of Alabama at Birmingham
Hui Min Leung: Wellman Center for Photomedicine, Massachusetts General Hospital
Guillermo J. Tearney: Wellman Center for Photomedicine, Massachusetts General Hospital
Alan S. Verkman: UCSF
Peter M. Haggie: UCSF
Kathleen Scott: University of Iowa
Douglas Bartels: University of Iowa
David K. Meyerholz: University of Iowa
Steven M. Rowe: University of Alabama at Birmingham
Xiaoming Liu: University of Iowa
Ziying Yan: University of Iowa
Adam L. Haber: Harvard T. H. Chan School of Public Health
Xingshen Sun: University of Iowa
John F. Engelhardt: University of Iowa

Nature, 2023, vol. 621, issue 7980, 857-867

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-023-06549-9 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:621:y:2023:i:7980:d:10.1038_s41586-023-06549-9

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-06549-9

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().