Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165200 | GEO | 2021/01/20
REPOSITORIES: GEO
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Project description:The SARS-CoV-2 virus has already caused over a million COVID-19 cases and over fifty-thousand deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 virus using human disease-relevant cells and tissues to understand key features of virus biology. We present a platform comprised of nine different cell and organoid derivatives from human pluripotent stem cells (hPSCs) representing all three primary germ layers, including lung progenitors and alveolar type II (AT2) cells, pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, and both cortical and dopaminergic neurons. We systematically probed which cell types are permissive to SARS-CoV-2 infection. Human pancreatic beta cells and hepatocytes were strikingly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and liver organoids. Both in vitro and in a humanized mouse model, human lung progenitors and AT2 cells express the ACE2 viral receptor and were highly permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived pancreatic and lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection. Therefore, hPSC-derived cells phenocopy human COVID-19 disease and provide a valuable resource to understand SARS-CoV-2 biology and search for novel therapeutics.
2020-06-11 | GSE147903 | GEO
Project description:Human transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, is exerting a massive health and socioeconomic burden. The virus infects pneumocytes, also known as alveolar epithelial type 2 (AT2) cells, leading to impaired gas exchange and acute lung injury, but the mechanisms driving infection and pathology are unclear. Here, we report a quantitative phosphoproteomic time-course survey of a validated human AT2 cell model, derived from induced pluripotent stem cells (iPSCs), that reveals rapid, profound and switch-like rewiring of lung cell functional modules upon SARS-CoV-2 infection. Maladaptive responses driven by viral propagation include altered host cell signaling pathways, remodeled host translational processes, impaired RNA processing, cytoskeletal-microtubule disruption coincident with interphase arrest, and a pronounced innate immune response. Our study provides a data-rich resource that defines the native host systems hijacked by SARS-CoV-2 and potential therapeutic avenues for COVID-19.
2020-11-20 | PXD020183 | Pride
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic and the lack of therapeutics hinders pandemic control. Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces tissue pathology in the lung remains elusive. Here we describe a high-throughput-based platform to generate tens of thousands of self-organizing, nearly identical, and genetically matched human lung buds derived from human pluripotent stem cells (hPSCs) cultured on confined geometries on micropattern chips. Strikingly, in vitro-derived human lung buds resemble fetal human lung tissue and display in vivo-like proximo-distal coordination of alveolar and airway tissue differentiation whose 3D epithelial self-organization is directed by the levels of KGF. Single-cell transcriptomics unveiled the cell identities and ontogeny of airway and alveolar tissue and the specification of WNThi cycling alveolar stem cells from alveolar progenitors. These synthetic human lung buds are susceptible to SARS-CoV-2 infection and can be used to track cell type-dependent susceptibilities to infection, intercellular transmission and cytopathology in airway and alveolar tissue in individual synthetic lung buds. We detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as targets of SARS-CoV-2. We used this platform to test neutralizing antibodies isolated from convalescent plasma that efficiently blocked SARS-CoV-2 infection and intercellular transmission. Our platform offers unlimited, rapid and scalable access to disease-relevant lung tissue that recapitulate human lung development and can be used to track SARS-CoV-2 infection and identify pre-clinical candidate therapeutics for COVID-19.
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Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial 5 infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral 10 infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.
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