Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells

Sano, Emi; Deguchi, Sayaka; Sakamoto, Ayaka; Mimura, Natsumi; Hirabayashi, Ai; Muramoto, Yukiko; Noda, Takeshi; Yamamoto, Takuya; Takayama, Kazuo

doi:10.1016/j.isci.2021.102428

Cited by 12 publications

(6 citation statements)

References 24 publications

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“…In this study, we revealed that SARS-CoV-2 virus could directly infect hESC. Sano et al reported that SARS-CoV-2 does not infect undifferentiated human iPSCs (Sano et al, 2021), the discrepancy between iPSC and hESCs needs to be further investigated. We found that hESCs expressed a low level of viral receptors ACE2 and TMPRSS2 but they still can contribute to the SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

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Evidence of Infection of Human Embryonic Stem Cells by SARS-CoV-2

Zeng

Xing²,

Ji³

et al. 2022

Front. Cell. Infect. Microbiol.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially described to target the respiratory system and now has been reported to infect a variety of cell types, including cardiomyocytes, neurons, hepatocytes, and gut enterocytes. However, it remains unclear whether the virus can directly infect human embryonic stem cells (hESCs) or early embryos. Herein, we sought to investigate this question in a cell-culture system of hESCs. Both the RNA and S protein of SARS-CoV-2 were detected in the infected hESCs and the formation of syncytium was observed. The increased level of subgenomic viral RNA and the presence of dsRNA indicate active replication of SARS-CoV-2 in hESCs. The increase of viral titers in the supernatants revealed virion release, further indicating the successful life cycle of SARS-CoV-2 in hESCs. Remarkably, immunofluorescence microscopy showed that only a small portion of hESCs were infected, which may reflect low expression of SARS-CoV-2 receptors. By setting |log2 (fold change)| > 0.5 as the threshold, a total of 1,566 genes were differentially expressed in SARS-CoV-2-infected hESCs, among which 17 interferon-stimulated genes (ISGs) were significantly upregulated. Altogether, our results provide novel evidence to support the ability of SARS-CoV-2 to infect and replicate in hESCs.

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Section: Discussionmentioning

confidence: 99%

“…Previously, human induced pluripotent stem cells overexpressing the SARS-CoV-2 viral receptor ACE2 (ACE2-iPSCs) or differentiated lineage cells derived from iPSCs were used in a SARS-CoV-2 study (Zhang et al, 2020;Sano et al, 2021). We are interested in whether hESC itself can be infected by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Infection of Human Embryonic Stem Cells by SARS-CoV-2

Zeng

Xing²,

Ji³

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Several researches utilizing stem cell-derived organoids have supplied valuable insight into the SARS-CoV-2 infection of diverse cell types and host responses, as well as aiding in the development of therapeutic candidates [ 16 , 21 , 24 , 31 , 42 , 49 , 50 , 51 , 52 ]. In vitro cell models have been used for evaluating aspects of viral entrance, life cycle, tropism, and pathogenesis of the COVID-19 infection.…”

Section: Discussionmentioning

confidence: 99%

Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids

Spitalieri

Centofanti

Murdocca

et al. 2022

Cells

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The global health emergency for SARS-CoV-2 (COVID-19) created an urgent need to develop new treatments and therapeutic drugs. In this study, we tested, for the first time on human cells, a new tetravalent neutralizing antibody (15033-7) targeting Spike protein and a synthetic peptide homologous to dipeptidyl peptidase-4 (DPP4) receptor on host cells. Both could represent powerful immunotherapeutic candidates for COVID-19 treatment. The infection begins in the proximal airways, namely the alveolar type 2 (AT2) cells of the distal lung, which express both ACE2 and DPP4 receptors. Thus, to evaluate the efficacy of both approaches, we developed three-dimensional (3D) complex lung organoid structures (hLORGs) derived from human-induced pluripotent stem cells (iPSCs) and resembling the in vivo organ. Afterward, hLORGs were infected by different SARS-CoV-2 S pseudovirus variants and treated by the Ab15033-7 or DPP4 peptide. Using both approaches, we observed a significant reduction of viral entry and a modulation of the expression of genes implicated in innate immunity and inflammatory response. These data demonstrate the efficacy of such approaches in strongly reducing the infection efficiency in vitro and, importantly, provide proof-of-principle evidence that hiPSC-derived hLORGs represent an ideal in vitro system for testing both therapeutic and preventive modalities against COVID-19.

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“…Functional and CoVint network analysis revealed MAGED1, FBXO7, ATAD3A, TECR, CCDC8, CDC14A, TERF2IP, FBXW7, RNF123, CAND1, USP7, SMC4, HIF1A, TRIM63, Transcriptomics pro le analysis of whole blood, pbmc and lung suggested signi cantly dysregulated levels of CREB3L1, SOX2, UBR4 and FLNC transcription factor. CREB3L1 is previously reported to be dysregulated in ER stress conditions during Covid-19 infections 25,26 whereas SOX2 is known to be a bronchus progenitor marker gene [27][28][29] and involved in cytokine-mediated signaling pathway 30 and play an important role in lung brosis 31,32 . Another common transcription factor identi ed from this analysis is UBR4 which is an E3 ubiquitin ligase and was found to be involved in the membrane morphogenesis autophagy process during the cytokine storm 33 .…”

Section: Network Analysismentioning

confidence: 99%

Transcriptome and SARS-CoV-2 biological network directed analysis for better therapeutic development

Sharma¹,

Sharma²,

Chandil³

2022

Preprint

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Background It has been almost 2 years since the first SARS-CoV-2 virus was first reported in the city of Wuhan. So far, 8 drugs are approved against Covid-19 by FDA, however, an active drug against multi-mutational Covid-19 is still missing. In this present study, we aim to identify the most crucial and highly correlated protein targets from the publicly available transcriptomics datasets. Methods Transcriptomics datasets were retrieved from Geo Omnibus (GEO). We use relevant datasets to identify the most significant and differentially expressed genes and integrated them into a Research graph called CovInt (a network of Covid-19) that includes all biological molecules associated in the network with their directionalities collected from publicly available and patient-derived multi-omics datasets from millions of unstructured and structured datasets such as publications, patents, grants, preclinical and clinical reports. CovInt utilizes powerful traversal, clustering and centrality algorithms to identify key connections in the pathophysiology of the disease and its treatments. Results Leveraging 3M + connections, important interactions among key 42 drugs, 962 biological processes and molecular functions, 926 pathways, 897 phenotypes, 7103 proteins, 61 tissues were identified. This narrowed interactome was explored further using PageRank, lovain detection & strongly connected components (SSC) algorithms. In our analysis 63, strongly connected communities were identified which gives us an understanding of hidden underlying mechanisms. We further explored this network to identify and triangulate the key proteins, metabolic pathways and associated risk factors that can regulate moderate to severe Covid-19 infections. Conclusions Our study suggests that CREB3L1, SOX2, UBR4, FLNC, ITPA, DLG3, ING4, TECR, NADH, SMAD, HUWE1, DDX17, CREBBP, RELA, HPSE, TRIM33, TNFSF13B are the key regulator proteins and involved in ER-stress, cytokine signaling, T-Cell activation, Activation of NLRP3 Inflammation by SARS-CoV-2, JAK-STAT, IL-4, IL-13 pathways, MAPK signaling pathways, Activation of NMDA receptor & postsynaptic events and TGF-β signaling pathways.

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Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells

Cited by 12 publications

References 24 publications

Evidence of Infection of Human Embryonic Stem Cells by SARS-CoV-2

Evidence of Infection of Human Embryonic Stem Cells by SARS-CoV-2

Two Different Therapeutic Approaches for SARS-CoV-2 in hiPSCs-Derived Lung Organoids

Transcriptome and SARS-CoV-2 biological network directed analysis for better therapeutic development

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