High resolution analysis of heterogeneous alveolar type II cells in emphysema and health reveals an airway origin of impaired alveolar regeneration

Emphysema is a major pathological phenotype of chronic obstructive pulmonary disease (COPD) that is characterized by progressive and irreversible alveolar tissue destruction caused by several stressors, such as tobacco smoke and air pollution. It remains incurable in part due to an incomplete understanding of cellular and molecular mechanisms underlying the failure of tissue repair. Here, we have generated a single cell RNA sequencing dataset of enriched epithelial cells from emphysematous parenchymal lung tissue of COPD patients and from healthy controls. Using this dataset, we performed high resolution analysis of 78,699 ATII cells and reveal novel ATII cell subsets in severe emphysema and health. These include two ATII sub-clusters expressing various secretoglobin mRNAs (SCGBpos) in COPD that present distinct transcriptomic profiles compared to healthy sub-clusters. These ATII sub-clusters that are present in human COPD are also found in a mouse emphysema model. Importantly, the COPD specific ATII cells from both species demonstrate airway origins and fail to undergo alveolar differentiation in organoid cultures, thereby suggesting that a common mechanism in emphysema pathogenesis.