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A human pluripotent stem cell-based model of SARS-CoV-2 infection reveals an ACE2-independent inflammatory activation of vascular endothelial cells through TLR4.
Ma, Zhangjing; Li, Xisheng; Fan, Rebecca L Y; Yang, Kevin Y; Ng, Calvin S H; Lau, Rainbow W H; Wong, Randolph H L; Ng, Kevin K; Wang, Chi Chiu; Ye, Peng; Fu, Zelong; Chin, Alex W H; Lai, M Y Alison; Huang, Yu; Tian, Xiao Yu; Poon, Leo L M; Lui, Kathy O.
  • Ma Z; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Li X; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Fan RLY; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Yang KY; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Ng CSH; Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Lau RWH; Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Wong RHL; Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Ng KK; Department of Surgery, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Wang CC; Department of Obstetrics & Gynaecology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; School of
  • Ye P; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Fu Z; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Chin AWH; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Lai MYA; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Huang Y; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
  • Tian XY; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
  • Poon LLM; School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; HKU-Pasteur Research Pole, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. Electronic address: llmpoon@hku.hk.
  • Lui KO; Department of Chemical Pathology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research In
Stem Cell Reports ; 17(3): 538-555, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1692861
ABSTRACT
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-1ß (IL-1ß) activation after viral exposure. Genome-wide, single-cell RNA-seq analyses further confirm activation of the TLR4/MAPK14/RELA/IL-1ß 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Toll-Like Receptor 4 / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / Models, Biological Type of study: Prognostic study Limits: Humans Language: English Journal: Stem Cell Reports Year: 2022 Document Type: Article Affiliation country: J.stemcr.2022.01.015

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Toll-Like Receptor 4 / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / Models, Biological Type of study: Prognostic study Limits: Humans Language: English Journal: Stem Cell Reports Year: 2022 Document Type: Article Affiliation country: J.stemcr.2022.01.015