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

Ameen A. Salahudeen, Shannon S. Choi, Arjun Rustagi, Junjie Zhu, Vincent Unen, Sean M. O, Ryan A. Flynn, Mar Margalef-Català, António J. M. Santos, Jihang Ju, Arpit Batish, Tatsuya Usui, Grace X. Y. Zheng, Caitlin E. Edwards, Lisa E. Wagar, Vincent Luca, Benedict Anchang, Monica Nagendran, Khanh Nguyen, Daniel J. Hart, Jessica M. Terry, Phillip Belgrader, Solongo B. Ziraldo, Tarjei S. Mikkelsen, Pehr B. Harbury, Jeffrey S. Glenn, K. Christopher Garcia, Mark M. Davis, Ralph S. Baric, Chiara Sabatti, Manuel R. Amieva, Catherine A. Blish (), Tushar J. Desai () and Calvin J. Kuo ()
Additional contact information
Ameen A. Salahudeen: Stanford University School of Medicine
Shannon S. Choi: Stanford University School of Medicine
Arjun Rustagi: Stanford University School of Medicine
Junjie Zhu: Stanford University School of Engineering, Department of Electrical Engineering
Vincent Unen: Stanford University School of Medicine
Sean M. O: Stanford University School of Medicine
Ryan A. Flynn: Stanford University
Mar Margalef-Català: Stanford University School of Medicine
António J. M. Santos: Stanford University School of Medicine
Jihang Ju: Stanford University School of Medicine
Arpit Batish: Stanford University School of Medicine
Tatsuya Usui: Stanford University School of Medicine
Grace X. Y. Zheng: 10x Genomics
Caitlin E. Edwards: University of North Carolina at Chapel Hill
Lisa E. Wagar: Stanford University School of Medicine
Vincent Luca: Stanford University School of Medicine
Benedict Anchang: Stanford University School of Medicine
Monica Nagendran: Stanford University School of Medicine
Khanh Nguyen: Stanford University School of Medicine
Daniel J. Hart: Stanford University School of Medicine
Jessica M. Terry: 10x Genomics
Phillip Belgrader: 10x Genomics
Solongo B. Ziraldo: 10x Genomics
Tarjei S. Mikkelsen: 10x Genomics
Pehr B. Harbury: Stanford University School of Medicine
Jeffrey S. Glenn: Stanford University School of Medicine
K. Christopher Garcia: Stanford University School of Medicine
Mark M. Davis: Stanford University School of Medicine
Ralph S. Baric: University of North Carolina at Chapel Hill
Chiara Sabatti: Stanford University School of Medicine
Manuel R. Amieva: Stanford University School of Medicine
Catherine A. Blish: Stanford University School of Medicine
Tushar J. Desai: Stanford University School of Medicine
Calvin J. Kuo: Stanford University School of Medicine

Nature, 2020, vol. 588, issue 7839, 670-675

Abstract: 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 the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.

Date: 2020
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DOI: 10.1038/s41586-020-3014-1

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