Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

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  • Salahudeen, Ameen A.
    • Other Affiliation: Stanford University School of Medicine
  • Choi, Shannon S.
    • Other Affiliation: Stanford University School of Medicine
  • Rustagi, Arjun
    • Other Affiliation: Stanford University School of Medicine
  • Zhu, Junjie
    • Other Affiliation: Stanford University School of Engineering
  • van Unen, Vincent
    • Other Affiliation: Stanford University School of Medicine
  • de la O, Sean M.
    • Other Affiliation: Stanford University School of Medicine
  • Flynn, Ryan A.
    • Other Affiliation: Stanford University
  • Margalef-Català, Mar
    • Other Affiliation: Stanford University School of Medicine
  • Santos, António J. M.
    • Other Affiliation: Stanford University School of Medicine
  • Ju, Jihang
    • Other Affiliation: Stanford University School of Medicine
  • Batish, Arpit
    • Other Affiliation: Stanford University School of Medicine
  • Usui, Tatsuya
    • Other Affiliation: Stanford University School of Medicine
  • Zheng, Grace X. Y.
    • Other Affiliation: 10x Genomics
  • Edwards, Caitlin E.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Wagar, Lisa E.
    • Other Affiliation: Stanford University School of Medicine
  • Luca, Vincent
    • Other Affiliation: Stanford University School of Medicine
  • Anchang, Benedict
    • Other Affiliation: Stanford University School of Medicine
  • Nagendran, Monica
    • Other Affiliation: Stanford University School of Medicine
  • Nguyen, Khanh
    • Other Affiliation: Stanford University School of Medicine
  • Hart, Daniel J.
    • Other Affiliation: Stanford University School of Medicine
  • Terry, Jessica M.
    • Other Affiliation: 10x Genomics
  • Belgrader, Phillip
    • Other Affiliation: 10x Genomics
  • Ziraldo, Solongo B.
    • Other Affiliation: 10x Genomics
  • Mikkelsen, Tarjei S.
    • Other Affiliation: 10x Genomics
  • Harbury, Pehr B.
    • Other Affiliation: Stanford University School of Medicine
  • Glenn, Jeffrey S.
    • Other Affiliation: Stanford University School of Medicine
  • Garcia, K. Christopher
    • Other Affiliation: Stanford University School of Medicine
  • Davis, Mark M.
    • Other Affiliation: Stanford University School of Medicine
  • Baric, Ralph S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Sabatti, Chiara
    • Other Affiliation: Stanford University School of Medicine
  • Amieva, Manuel R.
    • Other Affiliation: Stanford University School of Medicine
  • Blish, Catherine A.
    • Other Affiliation: Stanford University School of Medicine
  • Desai, Tushar J.
    • Other Affiliation: Stanford University School of Medicine
  • Kuo, Calvin J.
    • Other Affiliation: Stanford University School of Medicine
Abstract
  • The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate investigation of pathologies including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. We generated long-term feeder-free, chemically defined culture of distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential while basal cell organoids developed lumens lined by differentiated club and ciliated cells. Single cell analysis of basal organoid KRT5+ cells revealed a distinct ITGA6+ITGB4+ mitotic population whose proliferation further segregated to a TNFRSF12Ahi subfraction comprising ~10% of KRT5+ basal cells, residing in clusters within terminal bronchioles and exhibiting enriched clonogenic organoid growth activity. Distal lung organoids were created with apical-out polarity to display ACE2 on the exposed external surface, facilitating SARS-CoV-2 infection of AT2 and basal cultures and identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and establishes a facile in vitro organoid model for human distal lung infections including COVID-19-associated pneumonia.
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  • Article
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  • In Copyright
Journal title
  • Nature
Language
  • English
ISSN
  • 1476-4687

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