Single cell meta-analysis of EndMT and EMT state in COVID-19

Abstract

COVID-19 prognoses suggests that a proportion of patients develop fibrosis, but there is no evidence to indicate whether patients have progression of mesenchymal transition (MT) in the lungs. The role of MT during the COVID-19 pandemic remains poorly understood. Using single-cell RNA sequencing, we profiled the transcriptomes of cells from the lungs of healthy individuals (n = 45), COVID-19 patients (n = 58), and idiopathic pulmonary fibrosis (IPF) patients (n = 64) human lungs to map the entire MT change. This analysis enabled us to map all high-resolution matrix-producing cells and identify distinct subpopulations of endothelial cells (ECs) and epithelial cells as the primary cellular sources of MT clusters during COVID-19. For the first time, we have identied early and late subgroups of endothelial mesenchymal transition (EndMT) and epithelial-mesenchymal transition (EMT) using analysis of public databases for single-cell sequencing. We assessed epithelial subgroups by age, smoking status, and gender, and the data suggest that the proportional changes in EMT in COVID-19 are statistically significant. Further enumeration of early and late EMT suggests a correlation between invasive genes and COVID-19. Finally, EndMT is upregulated in COVID-19 patients and enriched for more inflammatory cytokines. Further, by classifying EndMT as early or late stages, we found that early EndMT was positively correlated with entry factors but this was not true for late EndMT. Exploring the MT state of may help to mitigate the fibrosis impact of SARS-CoV-2 infection.

An Overview of Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Canine Tumors: How Far Have We Come?

“…Interestingly, this virus is not only responsible for causing deaths due to its respiratory tropism and systemic dysregulation. Reports have described that SARS-CoV-2 infection in patients with cancer triggers the EMT phenomenon, thus favoring neoplastic malignant transformation [ 110 , 111 , 112 ]. In particular, a study by Lai and colleagues underlined the important oncogenic role of SARS-CoV-2 in triggering breast cancer metastasis through Snail upregulation [ 112 ].…”

Single cell ‘omic profiles of human aortic endothelial cellsin vitroand human atherosclerotic lesionsex vivoreveals heterogeneity of endothelial subtype and response to activating perturbations

“…We evaluated what pathways distinguished the Endothelial Cells 1 (Endo1) and Endothelial Cells 2 (Endo2) subtypes from our ex vivo meta-analysis (Figure 5C). We found Endo2 has an EndMT-related phenotype, with enrichment in mesenchymal pathways including NABA MATRISOME ASSOCIATED (M5885; p-value 1.6×10 -14 ), ECM organization (R-HSA-1474244; p-value 6×10 -17 ), skeletal system development (GO:0001501; p-value 3.4×10 -13 ), and network map of SARS-CoV-2 signaling pathway (52) (WP5115; p-value 1.3×10 -11 ) (Figure 5C-D). Additionally, we observe enrichment for inflammatory pathways in Endo2 including prostaglandin synthesis and regulation (WP98; p-value 1.2×10 -7 ), and complement and coagulation cascades (hsa04610; 1×10 -10 ) (Figure 5C-D) (55, 56).…”

“…Most genes significantly affected by perturbations in EC1 and EC2 were responsive to siERG, likely due to their more endothelial-like phenotypes compared to EC3 and EC4 (Figure 4A). siERG-affected genes in EC1 and EC2 were enriched in COVID-19 adverse outcome pathway (52) (WP4891; p-values 5×10 -9 and 8.3×10 -5 , for EC1-2 respectively) and AGE-RAGE signaling in diabetes (53) (hsa04933; p-values 8.9×10 -16 and 1.9×10 -20 , respectively), while EC3 siERG-perturbed genes are enriched with a unique metabolic profile demonstrated by enrichment in monosaccharide metabolic process (GO:0005996; p-value 1×10 -6 ), carbohydrate metabolic process (GO:0005975; p-value 6.6×10 -7 ), and aerobic glycolysis (WP4629; p-value 4.1×10 -5 ) (Figure 4D). In contrast, EC4 siERG-induced genes are enriched in positive regulation of angiogenesis (GO:0045766; p-value 4.5×10 -6 ), a function normally impaired in ERG -depleted endothelial cells (Figure 4D) (38).…”

“…Interestingly, IL1B but not siERG upregulated interferon signaling and viral responsive pathways (GO:0051607, p-value 1×10 -37 ; R-HSA-913531, p-value 1×10 -41 ). Shared IL1B- and siERG-upregulated genes were enriched in COVID-19 adverse outcome pathway (WP4891; p-value 1.9×10 -9 ) (52). Shared IL1B- and siERG-attenuated genes are enriched in several processes involving ribosomal proteins, including ribosome, cytoplasmic (CORUM:306; p-value 3.3×10 -7 ), cytoplasmic ribosomal proteins (WP477; p-value 5.3×10 -7 ), and peptide chain elongation (R-HSA-156902; p-value 5.9×10 -7 ) (Figure 4E).…”

Diabetic endothelial microangiopathy and pulmonary dysfunction

“…The vascular EG is disturbed by inflammation brought on by SARS-CoV-2 infection, as well as in people with hypertension, obesity, diabetes, cardiovascular disease, and current smokers. The elderly may be more susceptible to SARS-CoV-2 infection than younger people, and males are more likely to get the virus than females ( 11 ). The pulmonary interstitial develops aberrant shadows (multiple speckled shadows with a ground glass interstitial appearance) as a result of microvascular leaks caused by vascular glycocalyx failure.…”