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A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Author

Listed:
  • Emilie Crouchet

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Simonetta Bandiera

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Naoto Fujiwara

    (University of Texas Southwestern Medical Center)

  • Shen Li

    (Massachusetts General Hospital, Harvard Medical School)

  • Hussein El Saghire

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Mirian Fernández-Vaquero

    (German Cancer Research Center
    Heidelberg University)

  • Tobias Riedl

    (German Cancer Research Center
    Heidelberg University)

  • Xiaochen Sun

    (University of Texas Southwestern Medical Center)

  • Hadassa Hirschfield

    (University of Texas Southwestern Medical Center)

  • Frank Jühling

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Shijia Zhu

    (University of Texas Southwestern Medical Center)

  • Natascha Roehlen

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Clara Ponsolles

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Laura Heydmann

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Antonio Saviano

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil)

  • Tongqi Qian

    (University of Texas Southwestern Medical Center)

  • Anu Venkatesh

    (University of Texas Southwestern Medical Center)

  • Joachim Lupberger

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Eloi R. Verrier

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Mozhdeh Sojoodi

    (Massachusetts General Hospital, Harvard Medical School)

  • Marine A. Oudot

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • François H. T. Duong

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    University Hospital Basel, University of Basel)

  • Ricard Masia

    (Massachusetts General Hospital)

  • Lan Wei

    (Massachusetts General Hospital, Harvard Medical School)

  • Christine Thumann

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Sarah C. Durand

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Victor González-Motos

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Danijela Heide

    (German Cancer Research Center)

  • Jenny Hetzer

    (German Cancer Research Center)

  • Shigeki Nakagawa

    (University of Texas Southwestern Medical Center)

  • Atsushi Ono

    (Hiroshima University)

  • Won-Min Song

    (Icahn School of Medicine at Mount Sinai)

  • Takaaki Higashi

    (Kumamoto University)

  • Roberto Sanchez

    (Icahn School of Medicine at Mount Sinai)

  • Rosa S. Kim

    (Icahn School of Medicine at Mount Sinai)

  • C. Billie Bian

    (Icahn School of Medicine at Mount Sinai)

  • Karun Kiani

    (Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Tom Croonenborghs

    (Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology
    KU Leuven Technology Campus Geel, AdvISe)

  • Aravind Subramanian

    (Harvard Medical School)

  • Raymond T. Chung

    (Harvard Medical School)

  • Beate K. Straub

    (University Medicine, Johannes Gutenberg University)

  • Detlef Schuppan

    (Johannes Gutenberg University (JGU) Medical Center
    Harvard Medical School)

  • Maliki Ankavay

    (University of Lille, CNRS, Inserm, CHU Lille, Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille)

  • Laurence Cocquerel

    (University of Lille, CNRS, Inserm, CHU Lille, Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille)

  • Evelyne Schaeffer

    (CNRS UPR3572 Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC))

  • Nicolas Goossens

    (Geneva University Hospital)

  • Anna P. Koh

    (University of Texas Southwestern Medical Center)

  • Milind Mahajan

    (Icahn School of Medicine at Mount Sinai)

  • Venugopalan D. Nair

    (Icahn School of Medicine at Mount Sinai)

  • Ganesh Gunasekaran

    (Icahn School of Medicine at Mount Sinai)

  • Myron E. Schwartz

    (Icahn School of Medicine at Mount Sinai)

  • Nabeel Bardeesy

    (Massachusetts General Hospital Cancer Center; Harvard Medical School, Cambridge St. CPZN 4216)

  • Alex K. Shalek

    (Broad Institute of Harvard and Massachusetts Institute of Technology
    Institute for Medical Engineering Science & Department of Chemistry, MIT
    Ragon Institute of MGH, MIT and Harvard)

  • Orit Rozenblatt-Rosen

    (Broad Institute of Harvard and Massachusetts Institute of Technology
    Genentech, 1 DNA Way)

  • Aviv Regev

    (Broad Institute of Harvard and Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Genentech, 1 DNA Way)

  • Emanuele Felli

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil)

  • Patrick Pessaux

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil)

  • Kenneth K. Tanabe

    (Massachusetts General Hospital, Harvard Medical School)

  • Mathias Heikenwälder

    (German Cancer Research Center)

  • Catherine Schuster

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg)

  • Nathalie Pochet

    (Harvard Medical School
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Mirjam B. Zeisel

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1))

  • Bryan C. Fuchs

    (Massachusetts General Hospital, Harvard Medical School
    Ferring Pharmaceuticals Inc 4245 Sorrento Valley Blvd)

  • Yujin Hoshida

    (University of Texas Southwestern Medical Center)

  • Thomas F. Baumert

    (U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Université de Strasbourg
    Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil)

Abstract

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.

Suggested Citation

  • Emilie Crouchet & Simonetta Bandiera & Naoto Fujiwara & Shen Li & Hussein El Saghire & Mirian Fernández-Vaquero & Tobias Riedl & Xiaochen Sun & Hadassa Hirschfield & Frank Jühling & Shijia Zhu & Natas, 2021. "A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25468-9
    DOI: 10.1038/s41467-021-25468-9
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    Cited by:

    1. Atish Mukherji & Frank Jühling & Yogy Simanjuntak & Emilie Crouchet & Fabio Zompo & Yuji Teraoka & Alexandre Haller & Philippe Baltzinger & Soumith Paritala & Fahmida Rasha & Naoto Fujiwara & Cloé Gad, 2024. "An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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