Keratinizing Basal Cells and Peri-Goblet Cells Are Associated With Smoking and COPD in the Bronchial Epithelium

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Abstract Rationale: Airway remodeling associated with inflammation from cigarette smoke leads to several cellular and molecular changes across and within the major epithelial cell populations including goblet cell hyperplasia, a decrease in club cell numbers and damage to the exposed multiciliated cells, as well as other molecular changes within these cell-types. Histologically evident changes such as squamous metaplasia is also observed in the airways of smokers. However, how certain changes from smoking translate to the COPD phenotype, and if some of the changes are specific to COPD is lesser known at the cellular level. Here, we wish to understand the shared and independent cellular changes in the airway associated with COPD. Methods: We performed single nucleus RNA-seq (snRNA-seq) on frozen bronchial biopsies (n=72) from the DECAMP2 cohort that includes military veterans eligible for lung cancer screening based on their age and smoking history (> 20pk-yrs). Seurat clustering was used to identify major cell populations. Celda was used to identify modules of co-expressed genes that define each population. Sccomp was used to test for differences in cell state proportions across phenotypes. Results: While ciliated cells were significantly decreased in smokers with COPD as previously reported, we also observed an increase in deuterosomal cell population defined by CDC20B. Mucous and serous cells were significantly higher in smokers with COPD gold stage 2. A subset of basal cells with a keratinizing gene program (KRT13, KRT6A, SPRR3) was increased in the airways of smokers and patients with COPD. Similarly, we also see that peri-goblet secretory cells (CEACAM5+/MUC5AC-) are increasing in both COPD and smokers. We also observe depletion of SCGB1A1+ club cells in smokers with COPD. Conclusions: Overall, we established several epithelial cell states that are associated with smoking and COPD phenotypes. These changes may potentially indicate dysregulated pathways that may offer targets for therapeutic interventions.

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