The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single-cell resolution. Issue 2 (23rd August 2022)

• Record Type: Journal Article
• Authors: de Rooij, Laura P M H; Becker, Lisa M; Teuwen, Laure-Anne; Boeckx, Bram; Jansen, Sander; Feys, Simon; Verleden, Stijn; Liesenborghs, Laurens; Stalder, Anna K; Libbrecht, Sasha; Van Buyten, Tina; Philips, Gino; Subramanian, Abhishek; Dumas, Sébastien J; Meta, Elda; Borri, Mila; Sokol, Liliana; Dendooven, Amélie; Truong, Anh-Co K; Gunst, Jan; Van Mol, Pierre; Haslbauer, Jasmin D; Rohlenova, Katerina; Menter, Thomas; Boudewijns, Robbert; Geldhof, Vincent; Vinckier, Stefan; Amersfoort, Jacob; Wuyts, Wim; Van Raemdonck, Dirk; Jacobs, Werner; Ceulemans, Laurens J; Weynand, Birgit; Thienpont, Bernard; Lammens, Martin; Kuehnel, Mark; Eelen, Guy; Dewerchin, Mieke; Schoonjans, Luc; Jonigk, Danny; van Dorpe, Jo; Tzankov, Alexandar; Wauters, Els; Mazzone, Massimiliano; Neyts, Johan; Wauters, Joost; Lambrechts, Diether; Carmeliet, Peter;
• Is Part Of: Cardiovascular research. Volume 119:Issue 2(2023)
• Page Start: 520
• Page End: 535
• Publication Date: 2022-08-23
• Subjects: SARS-CoV-2 -- COVID-19 -- IPF -- Transcriptomics -- Single-nucleus RNA-seq -- Lung -- Endothelial cells; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac139
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Severe acute respiratory syndrome coronavirus-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage, and perturbed haemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date. Methods and results: We performed single-nucleus RNA-sequencing on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs, and 12 controls. The vascular fraction, comprising 38 794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137 746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor–ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF. Conclusions: This study uncovered novel insights into the abundance, expression patterns, and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions. Graphical Abstract: Graphical Abstract