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

Emilie Crouchet, Simonetta Bandiera, Naoto Fujiwara, Shen Li, Hussein El Saghire, Mirian Fernández-Vaquero, Tobias Riedl, Xiaochen Sun, Hadassa Hirschfield, Frank Jühling, Shijia Zhu, Natascha Roehlen, Clara Ponsolles, Laura Heydmann, Antonio Saviano, Tongqi Qian, Anu Venkatesh, Joachim Lupberger, Eloi R. Verrier, Mozhdeh Sojoodi, Marine A. Oudot, François H. T. Duong, Ricard Masia, Lan Wei, Christine Thumann, Sarah C. Durand, Victor González-Motos, Danijela Heide, Jenny Hetzer, Shigeki Nakagawa, Atsushi Ono, Won-Min Song, Takaaki Higashi, Roberto Sanchez, Rosa S. Kim, C. Billie Bian, Karun Kiani, Tom Croonenborghs, Aravind Subramanian, Raymond T. Chung, Beate K. Straub, Detlef Schuppan, Maliki Ankavay, Laurence Cocquerel, Evelyne Schaeffer, Nicolas Goossens, Anna P. Koh, Milind Mahajan, Venugopalan D. Nair, Ganesh Gunasekaran, Myron E. Schwartz, Nabeel Bardeesy, Alex K. Shalek, Orit Rozenblatt-Rosen, Aviv Regev, Emanuele Felli, Patrick Pessaux, Kenneth K. Tanabe, Mathias Heikenwälder, Catherine Schuster, Nathalie Pochet, Mirjam B. Zeisel, Bryan C. Fuchs (), Yujin Hoshida () and Thomas F. Baumert ()
Additional contact information
Emilie Crouchet: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Simonetta Bandiera: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
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
Mirian Fernández-Vaquero: German Cancer Research Center
Tobias Riedl: German Cancer Research Center
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
Shijia Zhu: University of Texas Southwestern Medical Center
Natascha Roehlen: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Clara Ponsolles: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Laura Heydmann: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Antonio Saviano: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
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
Eloi R. Verrier: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Mozhdeh Sojoodi: Massachusetts General Hospital, Harvard Medical School
Marine A. Oudot: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
François H. T. Duong: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
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
Sarah C. Durand: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Victor González-Motos: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
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
Tom Croonenborghs: Harvard Medical School
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
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
Orit Rozenblatt-Rosen: Broad Institute of Harvard and Massachusetts Institute of Technology
Aviv Regev: Broad Institute of Harvard and Massachusetts Institute of Technology
Emanuele Felli: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Patrick Pessaux: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
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
Nathalie Pochet: Harvard Medical School
Mirjam B. Zeisel: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Bryan C. Fuchs: Massachusetts General Hospital, Harvard Medical School
Yujin Hoshida: University of Texas Southwestern Medical Center
Thomas F. Baumert: U1110, Institut de Recherche sur les Maladies Virales et Hépatiques

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25468-9

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