Transgenic ferret models define pulmonary ionocyte diversity and function.

Autor: Yuan F; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Gasser GN; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Lemire E; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Montoro DT; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jagadeesh K; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Zhang Y; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Duan Y; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Ievlev V; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Wells KL; Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Rotti PG; Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Shahin W; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Winter M; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Rosen BH; Division of Pulmonary, Critical Care, Occupational, and Sleep Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Evans I; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Cai Q; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Yu M; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Walsh SA; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Acevedo MR; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Pandya DN; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Akurathi V; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Dick DW; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Wadas TJ; Department of Radiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Joo NS; Cystic Fibrosis Research Laboratory, Department of Psychology, Stanford University, Stanford, CA, USA.; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Wine JJ; Cystic Fibrosis Research Laboratory, Department of Psychology, Stanford University, Stanford, CA, USA., Birket S; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Fernandez CM; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Leung HM; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA., Tearney GJ; Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA., Verkman AS; Department of Medicine, UCSF, San Francisco, CA, USA.; Department of Physiology, UCSF, San Francisco, CA, USA., Haggie PM; Department of Medicine, UCSF, San Francisco, CA, USA.; Department of Physiology, UCSF, San Francisco, CA, USA., Scott K; Office of Animal Resources, University of Iowa, Iowa City, IA, USA., Bartels D; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Meyerholz DK; Department of Pathology, University of Iowa, Iowa City, IA, USA., Rowe SM; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Liu X; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Yan Z; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA., Haber AL; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA. ahaber@hsph.harvard.edu., Sun X; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. xingshen-sun@uiowa.edu., Engelhardt JF; Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. john-engelhardt@uiowa.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Sep; Vol. 621 (7980), pp. 857-867. Date of Electronic Publication: 2023 Sep 20.
DOI: 10.1038/s41586-023-06549-9
Abstrakt: 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 humans 1,2 , 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-Cre ERT2 ::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-Cre ERT2 ::CFTR L/L ). By comparing these models with cystic fibrosis ferrets 3,4 , 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-Cre ERT2 ::CFTR L/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl - and HCO 3 - . 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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