A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

By Daniel T. Montoro, Adam L. Haber, Moshe Biton, V. Vinarský, B. Lin, S. Birket, F. Yuan, Sijia Chen, H. Leung, Jorge Villoria and 19 more. Nature, 2018

1,057 citations recorded by the source corpus.

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. Single-cell RNA sequencing analysis identifies cell types and lineages in airway epithelium, including the pulmonary ionocyte, a new cell type predominantly expressing the cystic fibrosis gene CFTR.

Subfields: Epidemiology, Physiology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/41059b81660c98d7cf05f69190d695a18391f7b7

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Citations in the corpus

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis (2019, methodology): “In a recent report, single-cell RNA-seq was used to distinguish subpopulations of goblet and tufts cells in the mouse airways, and to identify a rare population of ionocytes (48).”
Lineage tracing on transcriptional landscapes links state to fate during differentiation (2018, background): “This approach can map the fate of cells from a continuous landscape of starting states and does not require isolation or labeling of specific prospective progenitor populations (2, 14).”
A molecular cell atlas of the human lung from single cell RNA sequencing (2019, background): “The 58 identified cell populations included 15 epithelial (clusters 1-15), 9 endothelial (16-24), 9 stromal (25-33), and 25 immune (34-58) populations, greater than the number of classical cell types in each compartment (11 epithelial, 5 endothelial, 7 stromal, 20 immune, and 2 neuronal cell types) ”
DNA methylation aging clocks: challenges and recommendations (2019, background): “In fact, single-cell techniques have recently recognized previously unknown pathologically relevant cell types, for example in the airway epithelium [173].”
SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues (2020, positive): “…enriched within olfactory epithelial gland cells, Muc5b+Scgb1c1+ goblet cells, basal epithelial cells, and myofibroblasts/pericytes (Bonferroni-corrected p < 0.01) (Figures 6B 12 Cell 181, 1–20, May 28, 2020 and S5B) (Brann et al., 2020; Dear et al., 1991; Montoro et al., 2018; Tepe et al., 2018).”