A human pluripotent stem cell-based model of SARS-CoV-2 infection reveals an ACE2-independent inflammatory activation of vascular endothelial cells through TLR4
| Autor: | Zhangjing Ma, Xisheng Li, Rebecca L.Y. Fan, Kevin Y. Yang, Calvin S.H. Ng, Rainbow W.H. Lau, Randolph H.L. Wong, Kevin K. Ng, Chi Chiu Wang, Peng Ye, Zelong Fu, Alex W.H. Chin, M.Y. Alison Lai, Yu Huang, Xiao Yu Tian, Leo L.M. Poon, Kathy O. Lui |
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| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
SARS-CoV-2 Gene Expression Profiling Interleukin-1beta NF-kappa B COVID-19 Endothelial Cells Cell Biology Biochemistry Models Biological Severity of Illness Index p38 Mitogen-Activated Protein Kinases Toll-Like Receptor 4 Genetics Human Umbilical Vein Endothelial Cells Humans Angiotensin-Converting Enzyme 2 Single-Cell Analysis Developmental Biology |
| Zdroj: | Stem cell reports. 17(3) |
| ISSN: | 2213-6711 |
| Popis: | To date, the direct causative mechanism of SARS-CoV-2-induced endotheliitis remains unclear. Here, we report that human ECs barely express surface ACE2, and ECs express less intracellular ACE2 than non-ECs of the lungs. We ectopically expressed ACE2 in hESC-ECs to model SARS-CoV-2 infection. ACE2-deficient ECs are resistant to the infection but are more activated than ACE2-expressing ones. The virus directly induces endothelial activation by increasing monocyte adhesion, NO production, and enhanced phosphorylation of p38 mitogen-associated protein kinase (MAPK), NF-κB, and eNOS in ACE2-expressing and -deficient ECs. ACE2-deficient ECs respond to SARS-CoV-2 through TLR4 as treatment with its antagonist inhibits p38 MAPK/NF-κB/ interleukin-1β (IL-1β) activation after viral exposure. Genome-wide, single-cell RNA-seq analyses further confirm activation of the TLR4/MAPK14/RELA/IL-1β axis in circulating ECs of mild and severe COVID-19 patients. Circulating ECs could serve as biomarkers for indicating patients with endotheliitis. Together, our findings support a direct role for SARS-CoV-2 in mediating endothelial inflammation in an ACE2-dependent or -independent manner. |
| Databáze: | OpenAIRE |
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