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 Yi; Ng, Calvin S. H.; Lau, Rainbow W. H.; Wong, Randolph H.L.; Ng, Kevin Kan-Shing; Wang, Chi Chiu; Ye, Peng; Fu, Zelong; Chin, Alex Wh; Lai, Mandy; Huang, Yü; Tian, Xiao Yu; Poon, Leo L M; Lui, Kathy O.

doi:10.1016/j.stemcr.2022.01.015

Cited by 27 publications

(28 citation statements)

References 42 publications

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“…Toll-like receptor 4 (TLR4) played an important role in the generation of an antiviral state after being infected with pathogenic viruses ( Boodhoo et al, 2022 ). A study of the human pluripotent stem cell–based model of SARS-CoV-2 infection demonstrated the involvement of TLR4 in the inflammatory activation of vascular endothelial cells ( Ma et al, 2022 ), and TLR4 was reported to contribute to anti-inflammatory effects and SARS-CoV-2 infection in vitro ( Numata and Voelker, 2022 ). Therefore, targeting the TLR4 inflammatory pathway could serve as a potential strategy in reducing inflammatory lung injury ( Bermudez et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

et al. 2022

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Until today, the coronavirus disease 2019 (COVID-19) pandemic has caused 6,043,094 deaths worldwide, and most of the mortality cases have been related to patients with long-term diseases, especially cancer. Autophagy is a cellular process for material degradation. Recently, studies demonstrated the association of autophagy with cancer development and immune disorder, suggesting autophagy as a possible target for cancer and immune therapy. Laminarin is a polysaccharide commonly found in brown algae and has been reported to have pharmaceutic roles in treating human diseases, including cancers. In the present report, we applied network pharmacology with systematic bioinformatic analysis, including gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, reactome pathway analysis, and molecular docking to determine the pharmaceutic targets of laminarin against COVID-19 and cervical cancer via the autophagic process. Our results showed that the laminarin would target ten genes: CASP8, CFTR, DNMT1, HPSE, KCNH2, PIK3CA, PIK3R1, SERPINE1, TLR4, and VEGFA. The enrichment analysis suggested their involvement in cell death, immune responses, apoptosis, and viral infection. In addition, molecular docking further demonstrated the direct binding of laminarin to its target proteins, VEGFA, TLR4, CASP8, and PIK3R1. The present findings provide evidence that laminarin could be used as a combined therapy for treating patients with COVID-19 and cervical cancer.

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Section: Discussionmentioning

confidence: 99%

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

et al. 2022

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“…we would An alternative explanation is that CSP-induced endothelial dysfunction occurs through an ACE2-independent pathway. Previous research has shown that adult endothelial cells have low 22 expression of ACE2 and that CSP-induced endothelial dysfunction can occur through TLR4 signaling 16 . In addition, CD34 + endothelial progenitors have also been shown to express ACE2 31 , so it is possible that the decrease in ACE2 in the CD34 + -hiPSC-EPs during the 7-day culture period is a normal part of the cells' maturation.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks

Stern

Monteleone

Zoldan

2022

Preprint

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With new daily discoveries about the long-term impacts of COVID-19 there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID-19. Here we demonstrate the utility of developing a model of endothelial dysfunction that utilizes induced pluripotent stem cell-derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID-19 on the endothelium. We found that treating these cell-laden hydrogels with SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity. Following treatment with the anti-inflammatory drug dexamethasone, we were able to prevent SARS-CoV-2 spike protein-induced endothelial dysfunction. In addition, we confirmed release of inflammatory cytokines associated with the COVID-19 cytokine storm. In conclusion, we have demonstrated that even in the absence of immune cells, we are able to use this 3D in vitro model for angiogenesis to reproduce COVID-19 induced endothelial dysfunction seen in clinical settings.

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“… 174 Recent studies have found that SARS‐CoV‐2 can promote IL‐1β production and mediate endothelial inflammation by activating the p38 MAPK/NF‐κB pathway via ACE2 or TLR4. 180 The p38 MAPK pathway is an important factor in mediating lung and heart injury in COVID‐19, and it promotes inflammation and CS development. Therefore, p38 MAPK inhibitors are a potential approach for the treatment of SARS‐CoV‐2 infection.…”

Section: Inflammatory Pathways In Covid‐19mentioning

confidence: 99%

“…P38 MAPK is able to affect the expression of various mi/lncRNAs and associated transcription factors, which are important for sterile inflammation and macrophage maturation, proinflammatory programming, and M2/Th2 polarization in COVID‐19 patients 174 . Recent studies have found that SARS‐CoV‐2 can promote IL‐1β production and mediate endothelial inflammation by activating the p38 MAPK/NF‐κB pathway via ACE2 or TLR4 180 . The p38 MAPK pathway is an important factor in mediating lung and heart injury in COVID‐19, and it promotes inflammation and CS development.…”

Section: Inflammatory Pathways In Covid‐19mentioning

confidence: 99%

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

Jiang

Zhao

Zhou

et al. 2022

MedComm

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The 2019 coronavirus disease (COVID‐19) pandemic has become a global crisis. In the immunopathogenesis of COVID‐19, SARS‐CoV‐2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID‐19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS‐CoV‐2 is important in providing otential therapeutic targets and treatment strategies against COVID‐19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID‐19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID‐19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID‐19.

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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

Cited by 27 publications

References 42 publications

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks

Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

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