Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

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  • Katsura, H.
    • Other Affiliation: Duke University School of Medicine
  • Sontake, V.
    • Other Affiliation: Duke University School of Medicine
  • Tata, A.
    • Other Affiliation: Duke University School of Medicine
  • Kobayashi, Y.
    • Other Affiliation: Duke University School of Medicine
  • Edwards, C.E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Heaton, B.E.
    • Other Affiliation: Duke University School of Medicine
  • Konkimalla, A.
    • Other Affiliation: Duke University School of Medicine
  • Asakura, T.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Mikami, Y.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Fritch, E.J.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Lee, P.J.
    • Other Affiliation: Duke University School of Medicine
  • Heaton, N.S.
    • Other Affiliation: Duke University School of Medicine
  • Boucher, R.C.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Randell, S.H.
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Baric, R.S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Tata, P.R.
    • Other Affiliation: Duke University School of Medicine
Abstract
  • Tata and colleagues report defined conditions for long-term expansion and differentiation of adult human primary alveolar stem cells. Cultured AT2s are conducive to SARS-CoV-2 infection and elicit transcriptome-wide changes that mirror COVID-19 histopathology, including upregulation of inflammatory responses, cell death, and downregulation of surfactant expression, leading to pneumocyte dysfunction. © 2020 Elsevier Inc.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.
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  • Article
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  • In Copyright
Journal title
  • Cell Stem Cell
Language
  • English
ISSN
  • 1934-5909

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