Smoking and Lung Defense: Single Cell Transcriptome Analysis of Human Small Airway Epithelium Demonstrates Smoking-Suppression of Club Cell Differentiation to a Defense Effector Role

Abstract

Rationale. Club cells, a small airway epithelium (SAE) secretory cell that expresses SCGB1A1 but not KRT5 (basal cell marker) or MUC5AC (goblet cell marker), play a central role in host defense of the human lung. In healthy, non-smoker SAE, club cell differentiation begins with basal stem/progenitor cells and proceeds through an intermediate cell phase before arriving at the mature club cell. In addition to their role in expressing host defense genes, club cells give rise to MUC5AC-positive goblet cells. Based on data demonstrating that ∼50% club cells express MUC5B, a secretory mucin critical for mucociliary clearance, we hypothesized that there may be subpopulations of club cells, each with distinct functions. Methods. The SAE was sampled from normal nonsmokers and healthy smokers by bronchoscopy and brushing. Using single cell