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1.
Stem Cell Rev Rep ; 17(6): 2107-2119, 2021 12.
Article in English | MEDLINE | ID: covidwho-1345193

ABSTRACT

The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation.


Subject(s)
COVID-19/virology , Cardiovascular System/virology , Pluripotent Stem Cells/virology , COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/virology , Cardiovascular System/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Humans , Lung/immunology , Lung/virology , Pandemics/prevention & control , Pluripotent Stem Cells/immunology , SARS-CoV-2/pathogenicity
2.
Stem Cell Reports ; 16(3): 385-397, 2021 03 09.
Article in English | MEDLINE | ID: covidwho-970134

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the coronavirus disease (COVID-19) outbreak that became a pandemic in 2020, causing more than 30 million infections and 1 million deaths to date. As the scientific community has looked for vaccines and drugs to treat or eliminate the virus, unexpected features of the disease have emerged. Apart from respiratory complications, cardiovascular disease has emerged as a major indicator of poor prognosis in COVID-19. It has therefore become of utmost importance to understand how SARS-CoV-2 damages the heart. Human pluripotent stem cell (hPSC) cardiovascular derivatives were rapidly recognized as an invaluable tool to address this, not least because one of the major receptors for the virus is not recognized by SARS-CoV-2 in mice. Here, we outline how hPSC-derived cardiovascular cells have been utilized to study COVID-19, and their potential for further understanding the cardiac pathology and in therapeutic development.


Subject(s)
COVID-19/pathology , COVID-19/virology , Heart/physiology , Heart/virology , Pluripotent Stem Cells/pathology , Pluripotent Stem Cells/virology , SARS-CoV-2/pathogenicity , Animals , Humans
3.
Antiviral Res ; 184: 104955, 2020 12.
Article in English | MEDLINE | ID: covidwho-871719

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is considered as the most significant global public health crisis of the century. Several drug candidates have been suggested as potential therapeutic options for COVID-19, including remdesivir, currently the only authorized drug for use under an Emergency Use Authorization. However, there is only limited information regarding the safety profiles of the proposed drugs, in particular drug-induced cardiotoxicity. Here, we evaluated the antiviral activity and cardiotoxicity of remdesivir using cardiomyocytes-derived from human pluripotent stem cells (hPSC-CMs) as an alternative source of human primary cardiomyocytes (CMs). In this study, remdesivir exhibited up to 60-fold higher antiviral activity in hPSC-CMs compared to Vero E6 cells; however, it also induced moderate cardiotoxicity in these cells. To gain further insight into the drug-induced arrhythmogenic risk, we assessed QT interval prolongation and automaticity of remdesivir-treated hPSC-CMs using a multielectrode array (MEA). As a result, the data indicated a potential risk of QT prolongation when remdesivir is used at concentrations higher than the estimated peak plasma concentration. Therefore, we conclude that close monitoring of the electrocardiographic/QT interval should be advised in SARS-CoV-2-infected patients under remdesivir medication, in particular individuals with pre-existing heart conditions.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/virology , Myocytes, Cardiac/virology , Pluripotent Stem Cells/cytology , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Amides/pharmacology , Animals , Antimalarials/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chlorocebus aethiops , Chloroquine/pharmacology , Electrocardiography , Flow Cytometry , Heart Diseases/complications , Humans , Hydroxychloroquine/pharmacology , Microscopy, Fluorescence , Myocytes, Cardiac/drug effects , Pluripotent Stem Cells/virology , Pyrazines/pharmacology , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Vero Cells , Viral Plaque Assay
4.
Cell Stem Cell ; 27(6): 937-950.e9, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-779663

ABSTRACT

Neurological complications are common in patients with COVID-19. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function is not well understood. Here, we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found that neurons and astrocytes were sparsely infected, but choroid plexus epithelial cells underwent robust infection. We optimized a protocol to generate choroid plexus organoids from hiPSCs and showed that productive SARS-CoV-2 infection of these organoids is associated with increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our findings provide evidence for selective SARS-CoV-2 neurotropism and support the use of hiPSC-derived brain organoids as a platform to investigate SARS-CoV-2 infection susceptibility of brain cells, mechanisms of virus-induced brain dysfunction, and treatment strategies.


Subject(s)
Choroid Plexus/virology , Neural Stem Cells/virology , Organoids/virology , Pluripotent Stem Cells/virology , SARS-CoV-2/physiology , Viral Tropism , Animals , Astrocytes/virology , Brain/cytology , Brain/virology , COVID-19/genetics , COVID-19/virology , Cells, Cultured , Gene Expression Regulation , Humans , Neurons/virology
5.
Cell Stem Cell ; 27(6): 962-973.e7, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-779662

ABSTRACT

A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.


Subject(s)
Alveolar Epithelial Cells/virology , Inflammation/virology , SARS-CoV-2/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Antiviral Agents/pharmacology , COVID-19/virology , Cells, Cultured , Drug Development , Enzyme Inhibitors/pharmacology , Humans , Models, Biological , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/virology , RNA-Seq , Serine Endopeptidases/metabolism , Virus Replication
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