Advancing lung organoids for COVID-19 research

Vaart, Jelte van der; Lamers, Mart M.; Haagmans, Bart L.; Clevers, Hans

doi:10.1242/dmm.049060

Cited by 40 publications

(33 citation statements)

References 81 publications

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“…Early expression studies either did not detect or detected low levels [87] or did not report [85] ACE2 protein expression in respiratory tissues, despite robust protein expression reported in other human tissues such as the intestine analyzed in parallel [85,87]. More recent studies have confirmed ACE2 protein expression and SARS-CoV-2 infections in respiratory epithelia, identifying the differentiated ciliated cells as the dominant cell type infected [21,29,32,88,89] (reviewed extensively elsewhere, e.g., [90][91][92]).…”

Section: Respiratory Tractmentioning

confidence: 99%

“…Organoids 2022, 1, FOR PEER REVIEW 7 [87] or did not report [85] ACE2 protein expression in respiratory tissues, despite robust protein expression reported in other human tissues such as the intestine analyzed in parallel [85,87]. More recent studies have confirmed ACE2 protein expression and SARS-CoV-2 infections in respiratory epithelia, identifying the differentiated ciliated cells as the dominant cell type infected [21,29,32,88,89] (reviewed extensively elsewhere, e.g., [90][91][92]). With the urgency to discover and evaluate therapies of severe respiratory damage in COVID-19, researchers have sought to establish human alveolar models of SARS-CoV-2 infection (Figure 4).…”

Section: Respiratory Tractmentioning

confidence: 99%

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Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which was classified as a pandemic in March 2020. As of 22 January 2022, globally more than 347 million cases of COVID-19 have been diagnosed, with 5.6 million deaths, making it the deadliest pandemic since the influenza pandemic in 1918. The clinical presentation of COVID-19-related illness spans from asymptomatic to mild respiratory symptoms akin to influenza infection to acute symptoms, including pneumonia necessitating hospitalisation and admission to intensive care units. COVID-19 starts in the upper respiratory tract and lungs but in severe cases can also involve the heart, blood vessels, brain, liver, kidneys and intestine. The increasing global health and economic burden of COVID-19 necessitates an urgent and global response. Understanding the functional characteristics and cellular tropism of SARS-CoV-2, and the pathogenesis that leads to multi-organ failure and death, has prompted an unprecedented adoption of organoid models. Successful drug discovery and vaccine development rely on pre-clinical models that faithfully recapitulate the viral life cycle and the host cell response to infection. Human stem cell-derived organoids fulfill these criteria. Here we highlight the role of organoids in the study of SARS-CoV-2 infection and modelling of COVID-19 pathogenesis.

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Section: Respiratory Tractmentioning

confidence: 99%

Section: Respiratory Tractmentioning

confidence: 99%

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

et al. 2022

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“…Since the field of primary epithelial cell models and AO is rapidly progressing, future applications of these models are endless. Currently these models are used for testing and developing effective treatments for SARS-CoV-2 ( 206 ). Another potential future application of primary HAEC is using species-specific cells to study the zoonotic potential of viruses.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Modelling of Respiratory Virus Infections in Human Airway Epithelial Cells – A Systematic Review

et al. 2021

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Respiratory tract infections (RTI) are a major cause of morbidity and mortality in humans. A large number of RTIs is caused by viruses, often resulting in more severe disease in infants, elderly and the immunocompromised. Upon viral infection, most individuals experience common cold-like symptoms associated with an upper RTI. However, in some cases a severe and sometimes life-threatening lower RTI may develop. Reproducible and scalable in vitro culture models that accurately reflect the human respiratory tract are needed to study interactions between respiratory viruses and the host, and to test novel therapeutic interventions. Multiple in vitro respiratory cell culture systems have been described, but the majority of these are based on immortalized cell lines. Although useful for studying certain aspects of viral infections, such monomorphic, unicellular systems fall short in creating an understanding of the processes that occur at an integrated tissue level. Novel in vitro models involving primary human airway epithelial cells and, more recently, human airway organoids, are now in use. In this review, we describe the evolution of in vitro cell culture systems and their characteristics in the context of viral RTIs, starting from advances after immortalized cell cultures to more recently developed organoid systems. Furthermore, we describe how these models are used in studying virus-host interactions, e.g. tropism and receptor studies as well as interactions with the innate immune system. Finally, we provide an outlook for future developments in this field, including co-factors that mimic the microenvironment in the respiratory tract.

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“…It seems conceivable that in our experimental conditions MeT5A survival is linked to the induction of Interferon response, which provokes the progressive clearance of infection over time. Apoptosis observed in vitro in other cell types (e.g., AT2 cells) may be influenced by specific experimental systems used, such as the use of feeder layer or organoids (Mulay et al, 2021;Katsura et al, 2020;Van Der Vaart et al, 2021). In these latter soft ECM-3D cultures often used to prevent AT2 cell differentiation, the induction of apoptosis may be relatively favored (Zhang et al, 2011;Halder et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

Matusali

Trionfetti

Bordoni

et al. 2021

Front. Mol. Biosci.

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Although lung fibrosis has a major impact in COVID-19 disease, its pathogenesis is incompletely understood. In particular, no direct evidence of pleura implication in COVID-19-related fibrotic damage has been reported so far. In this study, the expression of epithelial cytokeratins and Wilms tumor 1 (WT1), specific markers of mesothelial cells (MCs), was analyzed in COVID-19 and unrelated pleura autoptic samples. SARS-CoV-2 replication was analyzed by RT-PCR and confocal microscopy in MeT5A, a pleura MC line. SARS-CoV-2 receptors were analyzed by RT-PCR and western blot. Inflammatory cytokines from the supernatants of SARS-CoV-2-infected MeT5A cells were analysed by Luminex and ELLA assays. Immunohistochemistry of COVID-19 pleura patients highlighted disruption of pleura monolayer and fibrosis of the sub-mesothelial stroma, with the presence of MCs with fibroblastoid morphology in the sub-mesothelial stroma, but no evidence of direct infection in vivo. Interestingly, we found evidence of ACE2 expression in MCs from pleura of COVID-19 patients. In vitro analysis shown that MeT5A cells expressed ACE2, TMPRSS2, ADAM17 and NRP1, plasma membrane receptors implicated in SARS-CoV-2 cell entry and infectivity. Moreover, MeT5A cells sustained SARS-CoV-2 replication and productive infection. Infected MeT5A cells produced interferons, inflammatory cytokines and metalloproteases. Overall, our data highlight the potential role of pleura MCs as promoters of the fibrotic reaction and regulators of the immune response upon SARS-CoV-2 infection.

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Advancing lung organoids for COVID-19 research

Cited by 40 publications

References 81 publications

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

Organoid Models of SARS-CoV-2 Infection: What Have We Learned about COVID-19?

In Vitro Modelling of Respiratory Virus Infections in Human Airway Epithelial Cells – A Systematic Review

Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

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