The development of high-throughput single-cell RNA sequencing (scRNA-seq) has provided a new research tool to obtain gene expression profiles at single-cell resolution and identify novel cellular phenotypes in lung diseases. To elucidate the cell-specific mechanisms contributing to COPD pathogenesis, we used scRNA-seq to dissect cellular and molecular features of COPD and elucidate differences in the proportions and transcriptional phenotypes of epithelial cells between COPD patients, non-COPD smokers, and never-smokers. We sequenced 57,755 cells and achieved, on average, a sequencing depth of 112,482 reads per cell and 1,693 genes per cell. While epithelial components in never-smokers were relatively uniform, the smoker groups presented with extensive heterogeneity in epithelial cells, particularly in the alveolar type 2 (AT2) lineages. Notably, we identified a novel subpopulation of AT2 epithelial cells that emerged in COPD patients, and specifically expressed PD-L1 and a number of chemokines such as CXCL1 and CCL2. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred increased intercellular networks of inflammatory AT2 cells with immune and stromal cell populations. Our analysis reveals a unique cellular differentiation pathway and function underlying the biological and clinical characteristics of COPD pathogenesis.
