Cellular and molecular heterogeneities and signatures, and pathological trajectories of fatal COVID-19 lungs defined by spatial single-cell transcriptome analysis
Cellular and molecular heterogeneities and signatures, and pathological trajectories of fatal COVID-19 lungs defined by spatial single-cell transcriptome analysis
Abstract Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. Here, we examined postmortem COVID-19 lung tissues by spatial single-cell transcriptome analysis (SSCTA). We identified 18 major parenchymal and immune cell types, all of which are infected by SARS-CoV-2. Compared to the non-COVID-19 control, COVID-19 lungs have reduced alveolar cells (ACs), and increased innate and adaptive immune cells. Additionally, 19 differentially expressed genes in both infected and uninfected cells across the tissues mirror the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that are correlated with high cell densities (HIHD). The HIHD regions express high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2, and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration that have increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, echoing the tissue damage and wound healing processes. Sparse non- negative matrix factorization (SNMF) analysis of neighborhood cell type composition (NCTC) features identified 7 signatures that capture structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A progresses with primarily increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B is marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions are marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations primarily consisting of myofibroblasts. Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-2-SMAD2/3 pathways in these cells, which likely mediate the upregulation of COL1A1 and COL1A2, and excessive fibrosis in the lung tissues. Together, this study provides an SSCTA atlas of cellular and molecular signatures of fatal COVID-19 lungs, revealing the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology.
Huang Yufei、Flores Mario、Hasib Md Musaddaqul、Liu Zhentao、Das Arun、Galloway Hugh、Sica Gabriel L、Sordillo Emilia Mia、Gao Shou-Jiang、Grimes Zachary、Ramos da Silva Suzane、Chen Luping、Meng Wen、Chiu Yu-Chiao、Rivera Karla Paniagua、Bryce Clare、Paniz-Mondolfi Alberto、Cordon-Cardo Carlos
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Medicine, University of Pittsburgh School of Medicine||Department of Electrical and Computer Engineering, Swanson School of Engineering, University of PittsburghDepartment of Electrical and Computer Engineering, KLESSE School of Engineering and Integrated Design, University of Texas at San AntonioCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Medicine, University of Pittsburgh School of MedicineCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Electrical and Computer Engineering, Swanson School of Engineering, University of PittsburghCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Medicine, University of Pittsburgh School of MedicineCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Electrical and Computer Engineering, Swanson School of Engineering, University of PittsburghDepartment of Pathology, University of Pittsburgh School of MedicineDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount SinaiCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Microbiology and Molecular Genetics, University of Pittsburgh School of MedicineDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount SinaiCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Microbiology and Molecular Genetics, University of Pittsburgh School of MedicineCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Microbiology and Molecular Genetics, University of Pittsburgh School of MedicineCancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine||Department of Microbiology and Molecular Genetics, University of Pittsburgh School of MedicineDepartment of Medicine, University of Pittsburgh School of Medicine||Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh School of MedicineDepartment of Electrical and Computer Engineering, KLESSE School of Engineering and Integrated Design, University of Texas at San AntonioDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount SinaiDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount SinaiDepartment of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai
基础医学细胞生物学分子生物学
SSCTAspatial single-cell transcriptome analysisCOVID-19coronavirus disease 2019SARS-CoV-2SNMFsparse non-negative matrix factorization analysisNCTCneighborhood cell type composition analysistrajectory inferenceorganizing pneumoniafibrosisIL6-STAT3TGF-β-SMAD2/3
Huang Yufei,Flores Mario,Hasib Md Musaddaqul,Liu Zhentao,Das Arun,Galloway Hugh,Sica Gabriel L,Sordillo Emilia Mia,Gao Shou-Jiang,Grimes Zachary,Ramos da Silva Suzane,Chen Luping,Meng Wen,Chiu Yu-Chiao,Rivera Karla Paniagua,Bryce Clare,Paniz-Mondolfi Alberto,Cordon-Cardo Carlos.Cellular and molecular heterogeneities and signatures, and pathological trajectories of fatal COVID-19 lungs defined by spatial single-cell transcriptome analysis[EB/OL].(2025-03-28)[2025-05-08].https://www.medrxiv.org/content/10.1101/2023.02.24.23286388.点此复制
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