Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
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Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor type-2 (ACE2) and can be infected with virus. Transcriptome and histological analysis of infected alveolospheres mirror features of COVID-19 lungs, including emergence of interferon (IFN)-mediated inflammatory responses, loss of surfactant proteins, and apoptosis. Treatment of alveolospheres with IFNs recapitulates features of virus infection, including cell death. In contrast, alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-2. Human stem cell-based alveolospheres, thus, provide novel insights into COVID-19 pathogenesis and can serve as a model for understanding human respiratory diseases.
Published Version (Please cite this version)10.1016/j.stem.2020.10.005
Publication InfoKatsura, Hiroaki; Sontake, Vishwaraj; Tata, Aleksandra; Kobayashi, Yoshihiko; Edwards, Caitlin E; Heaton, Brook E; ... Tata, Purushothama Rao (2020). Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction. Cell stem cell. 10.1016/j.stem.2020.10.005. Retrieved from https://hdl.handle.net/10161/21706.
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Assistant Research Professor of Molecular Genetics and Microbiology
Assistant Professor of Molecular Genetics and Microbiology
Professor of Medicine
My overall research interests are in acute and chronic oxidant-induced lung injury and repair, specifically the distinct roles of stress-response pathways depending on the lung compartment or cell type(s) involved and their regulation by the immune system. Using models of inhaled toxins, such as high oxygen concentrations, cigarette smoke, and microbes, we discovered previously unrecognized mechanistic roles for innate immune receptors, TLR4-NLRP3, mitochondrial health and cell fate, su
Assistant Professor of Cell Biology
Lung regenerationLung stem cellsCell plasticityOrganoid modelsLung FibrosisSingle Cell Biology
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