Characterization of the COPD alveolar niche using single-cell RNA sequencing

Maor Sauler,Klaus H Jensen,John E Mcdonough,Micha Sam Brickman Raredon ,Cristian Coarfa,Pascal Timshel ,Sarah G Chu,José L Gómez ,Norihito Omote,Jonas C Schupp,Carlos Cosme,Rhiannon B Werder,Matthew J Robertson,Taylor Adams ,Maurizio Chioccioli,Tao Yang,Naftali Kaminski,Thomas Bärnthaler ,Laura E Niklason,Andrew Wilson ,Ehab Ayaub ,Sergio Poli,Clemente J Britto,Neeharika Kothapalli,Jessica Nouws,Iván O Rosas

doi:10.1038/s41467-022-28062-9

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete
Our analysis focused on 17 patients with advanced COPD, and 15 age-matched controls (Fig. 1A)
Individuals with COPD had a mean ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) of 0.36 ± 0.05 and a mean FEV1 percent predicted of 21.0 ± 5.0

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. We detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. These findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD. The pathogenic cascade of COPD is initiated by repetitive insults to epithelial and endothelial cells within the distal airways and alveolar niche. This engenders activation of diverse cellular processes including immune cell infiltration, extracellular matrix proteolysis, cellular metabolic dysfunction, loss of proteostasis, DNA damage, autophagy, cellular senescence, and activation of regulated cell death pathways[3,6,7]. We identify a subpopulation of high metallothionein-expressing alveolar macrophages in the COPD lung

Methods

Results

Conclusion