Single-cell RNA sequencing identifies aberrant transcriptional profiles of cellular populations and altered alveolar niche signalling networks in Chronic Obstructive Pulmonary Disease (COPD)

Abstract

ABSTRACTChronic Obstructive Pulmonary Disease (COPD) pathogenesis involves a failure to maintain alveolar homeostasis due to repetitive injury and inflammation. In order to improve our understanding of cell-specific mechanisms contributing to COPD pathogenesis, we analysed single-cell RNA sequencing (scRNAseq) profiles of explanted parenchymal lung tissue from 17 subjects with advanced COPD requiring transplant and 15 control donor lungs. We identified a subpopulation of alveolar type II epithelial cells that uniquely express HHIP and have aberrant stress tolerance profiles in COPD. Amongst endothelial cells, we identified overlapping and unique shifts in transcriptional profiles of endothelial subtypes that may contribute to vascular inflammation and susceptibility to injury. We also identified population composition changes amongst alveolar macrophages. Finally, application of integrative analyses to our scRNAseq data identified cell-specific contributions to COPD heritability and dysfunctional cell-cell communication pathways that occur within the COPD alveolar niche. These findings provide cell type-specific resolution of transcriptional changes associated with advanced COPD that may underlie disease pathogenesis.