Abstract
Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. Here, through single cell RNA-sequencing analysis of the tracheal epithelium from smokers and non-smokers, we generate a comprehensive atlas of epithelial cell types and states, connect these into lineages, and define cell-specific responses to smoking. Our analysis infers multi-state lineages that develop into surface mucus secretory and ciliated cells and then contrasts these to the unique specification of submucosal gland (SMG) cells. Accompanying knockout studies reveal that tuft-like cells are the likely progenitor of both pulmonary neuroendocrine cells and CFTR-rich ionocytes. Our smoking analysis finds that all cell types, including protected stem and SMG populations, are affected by smoking through both pan-epithelial smoking response networks and hundreds of cell-specific response genes, redefining the penetrance and cellular specificity of smoking effects on the human airway epithelium.
Highlights
Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases
We identified a core response to smoking that encompassed genes upregulated or downregulated in at least five cell types (Fig. 2a). Among this core response were polycyclic aromatic hydrocarbon metabolizing genes (e.g., CYP1B1), S100 family genes, markers of squamous metaplasia (e.g., KRT14 and KRT17), and interferon and chemokine inflammatory signaling (Fig. 2b, Supplementary Fig. 3c). These results suggest that previously reported responses to smoking, which include toxin metabolism, macrophage recruitment, and squamous metaplasia, are a joint effort conducted across epithelial cell types
Our data reveal that during both in vitro differentiation and in vivo homeostasis, ciliated cells derive from a secretory progenitor through multiple, discrete, transcriptional states, regulated by a suite of transcription factor (TF) that include forkhead box N4 gene (FOXN4), which we identify in humans as a regulator of this earliest ciliating state
Summary
Cigarette smoke first interacts with the lung through the cellularly diverse airway epithelium and goes on to drive development of most chronic lung diseases. The human airway epithelium is a complex, cellularly diverse tissue that has a critical role in respiratory health by facilitating air transport, barrier function, mucociliary clearance, and the regulation of lung immune responses These airway functions are accomplished through interactions among a functionally diverse set of both abundant (ciliated, mucus secretory, and basal stem) and rare cell types (tuft, pulmonary neuroendocrine, and ionocyte), which compose the airway surface epithelium. Gene expression and histological studies of the airway epithelium have demonstrated that both molecular dysfunction and cellular imbalance due to shifting cell composition in the epithelium are common features of most chronic lung diseases, including asthma[3] and chronic obstructive pulmonary disease[4] (COPD) This cellular remodeling is largely mediated by interaction of the epithelium with inhaled agents such as cigarette smoke, air pollution, and allergens, which are risk factors for these diseases. We use single-cell RNA-sequencing (scRNA-seq) to define the transcriptional cell types and states of the tracheal airway epithelium in smokers and non-smokers, infer the lineage relationships among these cells, and determine the influence of cigarette smoke on individual surface and SMG airway epithelial cell types with single-cell resolution
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