A revised airway epithelial hierarchy includes CFTR-expressing ionocytes
Name
nihms-977247.pdf
Description
Accepted version
Size
6.56 MB
Format
Adobe PDF
Checksum (MD5)
27756efc520b0b54dc0a6c0f42a9fc97
Author(s)
Regev, Aviv
Date Issued
August 2018
Journal
Nature
Publisher
Springer Nature
Citation
Montoro, Daniel T. et al. “A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.” Nature 560 (2018): 319-324 © 2018 The Author(s)
Version
Author's final manuscript
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 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/S41586-018-0393-7
