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Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2.

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Affiliations

  • 1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; GENOME INSIGHT, Inc., Daejeon 34051, Republic of Korea.
      Authors
    • Youk J 1
    • Ju YS 1
    (2 authors)
  • 2. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
      Authors
    • Kim T 2
    • Yi K 2
    • Kim SY 2
    (3 authors)
  • 3. Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 A0W, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EL, UK.
      Authors
    • Evans KV 3
    • Lee JH 3
    (2 authors)
  • 4. Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea.
      Authors
    • Jeong YI 4
    • Kim JH 4
    • Choi BS 4
    (3 authors)
  • 5. BioMedical Research Center, Korea Advanced institute of Science and Technology, Daejeon 34141, Republic of Korea.
      Authors
    • Hur Y 5
    (1 author)
    • Show all (12)

ORCIDs linked to this article

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Cell Stem Cell, 21 Oct 2020, 27(6):905-919.e10
https://doi.org/10.1016/j.stem.2020.10.004 PMID: 33142113 PMCID: PMC7577700

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Abstract 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term, three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and proinflammatory genes in infected hAT2 cells, indicating a robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2 and the application of defined 3D hAT2 cultures as models for respiratory diseases.

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Read article at publisher's site: https://doi.org/10.1016/j.stem.2020.10.004

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    Funding 

    Funders who supported this work.

    Biotechnology and Biological Sciences Research Council (2)

    Biotechnology and Biological Sciences Research Council Industrial CASE (1)

    European Research Council (1)

    Human Frontier Science Program (1)

    Institute for Basic Science (1)

    • Grant ID: IBS-R025-D1

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    Korea Health Industry Development Institute

      Korea Health Technology R&D Project

        Medical Research Council (2)

        Ministry of Health & Welfare, Republic of Korea (1)

        • Grant ID: HI14C1277

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        Ministry of Science and ICT of Korea

          National Research Foundation of Korea (2)

          • Grant ID: NRF-2020R1A3B2078973

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          • Grant ID: NRF-2019H1D3A2A02061168

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          Research Program 2020 funded by Seoul National University College of Medicine Research Foundation (1)

          • Grant ID: 800-20200516 to Y.T.K.

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          Research of Korea Centers for Disease Control and Prevention (1)

          • Grant ID: 2019-NI069-00

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          Suh Kyungbae Foundation (1)

          • Grant ID: SUHF-18010082

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          Wellcome Trust (1)

          • Grant ID: 107633/Z/15/Z

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          Wellcome and the Royal Society (1)

          • Grant ID: 107633/Z/15/Z

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