Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids

  1. Bing Zhao
  2. Chao Ni
  3. Ran Gao
  4. Yuyan Wang
  5. Li Yang
  6. Jinsong Wei
  7. Ting Lv
  8. Jianqing Liang
  9. Qisheng Zhang
  10. Wei Xu
  11. Youhua Xie
  12. Xiaoyue Wang
  13. Zhenghong Yuan
  14. Junbo Liang
  15. Rong Zhang
  16. Xinhua Lin

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Abstract

The newly emerged pandemic coronavirus, SARS-CoV-2, has posed a significant public health threat worldwide. However, the mode of virus transmission and tissue tropism is not well established yet. Recent findings of substantial liver damage in patients and ACE2+ cholangiocytes in healthy liver tissues prompted us to hypothesize that human liver ductal organoids could serve as a model to determine the susceptibility and mechanisms underlining the liver damage upon SARS-CoV-2 infection. By single-cell RNA sequencing, we found that long-term liver ductal organoid culture preserved the human specific ACE2+ population of cholangiocytes. Moreover, human liver ductal organoids were permissive to SARS-CoV-2 infection and support robust replication. Notably, virus infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, which could explain the bile acid accumulation and consequent liver damage in patients. These results indicate that control of liver damage caused directly by viral infection should be valued in treating COVID-19 patients. Our findings also provide an application of human organoids in investigating the tropism and pathogenesis of SARS-CoV-2, which would facilitate novel drug discovery.

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    SciScore for 10.1101/2020.03.16.990317: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The following antibodies were used: rabbit anti-ACE2 (Sino Biological Inc, 10108-RP01, 1:100), rabbit anti-SARS-CoV-2 N protein (Rockland, 200-401-A50,
    anti-ACE2
    suggested: (Enzo Life Sciences Cat# ALX-804-722-C100, RRID:AB_11180102)
    anti-SARS-CoV-2 N protein
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Virus was plaque-purified, propagated in Vero-E6 cells, and stored at –80°C for use.
    Vero-E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mouse primary liver ductal organoids were cultured from biliary ducts isolated from an 8-week-old C57BL/6 mouse.
    C57BL/6
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 17. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.03.16.990317 on bioRxiv