Transgenic ferret models define pulmonary ionocyte diversity and function

作者：Feng Yuan, Grace N. Gasser, Evan Lemire, Daniel T. Montoro, Karthik A. Jagadeesh, Yan Zhang, Yifan Duan, Vitaly Ievlev, Kristen L. Wells, Pavana G. Rotti, Weam Shahin, Michael C. Winter, Bradley H. Rosen, Idil A. Evans, Qian Cai, Miao Yu, Susan A. Walsh, Michael R. Acevedo, Darpan N. Pandya, Vamsidhar Akurathi, David Dick, Thaddeus J. Wadas, Nam Soo Joo, Jeffrey J. Wine, Susan E. Birket, Courtney M. Fernandez, Hui Min Leung, Guillermo J. Tearney, A. S. Verkman, Peter M. Haggie, Kathleen Scott, D Bartels, David K. Meyerholz, Steven M. Rowe, Xiaoming Liu, Ziying Yan, Adam L. Haber, Xingshen Sun, John F. Engelhardt · 发表于：Nature · 年份：2023 · DOI：10.1038/s41586-023-06549-9 · 被引用次数：75 · 研究领域：Cystic Fibrosis Research Advances、Neonatal Respiratory Health Research、Tracheal and airway disorders

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 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 fu...