A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.

Academic Article

Abstract

  • 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┬álocation; 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┬ácharacteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.
  • Published In

  • Nature  Journal
  • Keywords

  • Animals, Asthma, Cell Differentiation, Cell Lineage, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Cells, Female, Forkhead Transcription Factors, Gene Expression Profiling, Gene Expression Regulation, Goblet Cells, Humans, Lung, Male, Mice, Sequence Analysis, RNA, Single-Cell Analysis, Trachea
  • Digital Object Identifier (doi)

    Author List

  • Montoro DT; Haber AL; Biton M; Vinarsky V; Lin B; Birket SE; Yuan F; Chen S; Leung HM; Villoria J
  • Start Page

  • 319
  • End Page

  • 324
  • Volume

  • 560
  • Issue

  • 7718