Abstract

Background: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear.

Method: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19.

Results: Infected ALO-monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both.

Conclusions: Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines.

Funding: This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).

Data availability

Sequencing data have been deposited in GEO under accession codes GSE157055, and GSE157057.We have added the Data availability section in the main manuscript.

The following data sets were generated

Article and author information

Author details

  1. Courtney Tindle

    Department of Cellular and Molecular Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. MacKenzie Fuller

    Department of Cellular and Molecular Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6781-8710
  3. Ayden Fonseca

    Department of Cellular and Molecular Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sahar Taheri

    Department of Computer Science and Engineering, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stella-Rita Ibeawuchi

    Pathology, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nathan Beutler

    Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gajanan Dattatray Katkar

    Department of Cellular and Molecular Medicine, UCSD, SAN DIEGO, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Amanraj Claire

    Pathology, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Vanessa Castillo

    Department of Cellular and Molecular Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4182-8846
  10. Moises Hernandez

    Division of Cardiothoracic Surgery, UCSD, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7651-2673
  11. Hana Russo

    Pathology, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jason Duran

    7Division of Cardiology, Department of Internal Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Laura E Crotty Alexander

    Medicine, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5091-2660
  14. Ann Tipps

    Pathology, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Grace Lin

    Pathology, UCSD, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Patricia A Thistlethwaite

    Division of Cardiothoracic Surgery, UCSD, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Ranajoy Chattopadhyay

    Medicine, UCSD, San Diego, United States
    For correspondence
    rachatto72@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  18. Thomas F Rogers

    Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, United States
    For correspondence
    trogers@health.ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
  19. Debashis Sahoo

    Department of Computer Science and Engineering, UCSD, San Diego, United States
    For correspondence
    dsahoo@health.ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
  20. Pradipta Ghosh

    Department of Cellular and Molecular Medicine, UCSD, SAN DIEGO, United States
    For correspondence
    prghosh@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8917-3201
  21. Soumita Das

    Pathology, UCSD, San Diego, United States
    For correspondence
    sodas@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3895-3643

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (3R01DK107585-05S1)

  • Soumita Das

University of California, San Diego (UCOP-R00RG2642)

  • Pradipta Ghosh
  • Soumita Das

National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK107585-01A1)

  • Soumita Das

National Institute of Allergy and Infectious Diseases (R01-AI 155696)

  • Debashis Sahoo
  • Pradipta Ghosh
  • Soumita Das

National Institute of Allergy and Infectious Diseases (R01-AI141630)

  • Pradipta Ghosh

National Cancer Institute (CA100768)

  • Pradipta Ghosh

National Cancer Institute (CA160911)

  • Pradipta Ghosh

National Institute of General Medical Sciences (R01-GM138385)

  • Debashis Sahoo

National Heart, Lung, and Blood Institute (R01- HL32225)

  • Patricia A Thistlethwaite

University of California, San Diego (UCOP-R01RG3780)

  • Debashis Sahoo
  • Pradipta Ghosh
  • Soumita Das

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Deidentified lung tissues obtained during surgical resection, that were deemed excess by clinical pathologists, were collected using an approved human research protocol (IRB# 101590; PI: Thistlethwaite). Isolation and biobanking of organoids from these lung tissues were carried out using an approved human research protocol (IRB# 190105: PI Ghosh and Das) that covers human subject research at the UC San Diego HUMANOID Center of Research Excellence (CoRE). For all the deidentified human subjects, information including age, gender, and previous history of the disease, was collected from the chart following the rules of HIPAA and described in the Table.

Reviewing Editor

  1. Milica Radisic, University of Toronto, Canada

Publication history

  1. Received: January 10, 2021
  2. Accepted: August 11, 2021
  3. Accepted Manuscript published: August 13, 2021 (version 1)
  4. Version of Record published: September 24, 2021 (version 2)

Copyright

© 2021, Tindle et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Courtney Tindle
  2. MacKenzie Fuller
  3. Ayden Fonseca
  4. Sahar Taheri
  5. Stella-Rita Ibeawuchi
  6. Nathan Beutler
  7. Gajanan Dattatray Katkar
  8. Amanraj Claire
  9. Vanessa Castillo
  10. Moises Hernandez
  11. Hana Russo
  12. Jason Duran
  13. Laura E Crotty Alexander
  14. Ann Tipps
  15. Grace Lin
  16. Patricia A Thistlethwaite
  17. Ranajoy Chattopadhyay
  18. Thomas F Rogers
  19. Debashis Sahoo
  20. Pradipta Ghosh
  21. Soumita Das
(2021)
Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19
eLife 10:e66417.
https://doi.org/10.7554/eLife.66417
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