Single-cell transcriptomics reveal cell type-specific molecular changes and altered intercellular communications in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a common and heterogeneous respiratory disease, the molecular complexity of which remains poorly understood, as well as the mechanisms by which aging and smoking facilitate COPD development. Here, using single-cell RNA sequencing of more than 65,000 cells from COPD and age-stratified control lung tissues of donors with different smoking histories, we identified monocytes, club cells, and macrophages as the most disease-, aging-, and smoking-relevant cell types, respectively. Notably, we found these highly cell-type specific changes under different conditions converged on cellular dysfunction of the alveolar epithelium. Deeper investigations revealed that the alveolar epithelium damage could be attributed to the abnormally activated monocytes in COPD lungs, which could be amplified via exhaustion of club cell stemness as ages. Moreover, the enhanced intercellular communications in COPD lungs as well as the pro-inflammatory interaction between macrophages and endothelial cells indued by smoking could facilitate signaling between monocyte and the alveolar epithelium. Our findings complement the existing model of COPD pathogenesis by emphasizing the contributions of the previously less appreciated cell types, highlighting their candidacy as potential therapeutic targets for COPD.

scRNA-seq and scATAC-seq analyses highlight the role of TNF signaling in chronic obstructive pulmonary disease progression

“…Endothelial cells show overlapping and distinct transcriptional pro le shifts, possibly contributing to vascular in ammation and injury susceptibility in COPD [18] . As the most disease-, aging-, and smoking-relevant cell types, monocytes, club cells, and macrophages exhibit changes leading to alveolar epithelium dysfunction [19] . The populations with more differentially expressed genes were monocytes, macrophages, and ciliated epithelial cells, and QKI and IGFBP5 protein levels were found to be altered in the COPD lungs [20] .…”