A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.

Journal Article (Journal Article)

The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1+ pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term 'hillocks'; and disease-relevant subsets of tuft and goblet cells. We developed 'pulse-seq', combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.

Full Text

Duke Authors

Cited Authors

  • Montoro, DT; Haber, AL; Biton, M; Vinarsky, V; Lin, B; Birket, SE; Yuan, F; Chen, S; Leung, HM; Villoria, J; Rogel, N; Burgin, G; Tsankov, AM; Waghray, A; Slyper, M; Waldman, J; Nguyen, L; Dionne, D; Rozenblatt-Rosen, O; Tata, PR; Mou, H; Shivaraju, M; Bihler, H; Mense, M; Tearney, GJ; Rowe, SM; Engelhardt, JF; Regev, A; Rajagopal, J

Published Date

  • August 2018

Published In

Volume / Issue

  • 560 / 7718

Start / End Page

  • 319 - 324

PubMed ID

  • 30069044

Pubmed Central ID

  • PMC6295155

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/s41586-018-0393-7


  • eng

Conference Location

  • England