TY - JOUR
T1 - A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
AU - Crouchet, Emilie
AU - Bandiera, Simonetta
AU - Fujiwara, Naoto
AU - Li, Shen
AU - El Saghire, Hussein
AU - Fernández-Vaquero, Mirian
AU - Riedl, Tobias
AU - Sun, Xiaochen
AU - Hirschfield, Hadassa
AU - Jühling, Frank
AU - Zhu, Shijia
AU - Roehlen, Natascha
AU - Ponsolles, Clara
AU - Heydmann, Laura
AU - Saviano, Antonio
AU - Qian, Tongqi
AU - Venkatesh, Anu
AU - Lupberger, Joachim
AU - Verrier, Eloi R.
AU - Sojoodi, Mozhdeh
AU - Oudot, Marine A.
AU - Duong, François H.T.
AU - Masia, Ricard
AU - Wei, Lan
AU - Thumann, Christine
AU - Durand, Sarah C.
AU - González-Motos, Victor
AU - Heide, Danijela
AU - Hetzer, Jenny
AU - Nakagawa, Shigeki
AU - Ono, Atsushi
AU - Song, Won Min
AU - Higashi, Takaaki
AU - Sanchez, Roberto
AU - Kim, Rosa S.
AU - Bian, C. Billie
AU - Kiani, Karun
AU - Croonenborghs, Tom
AU - Subramanian, Aravind
AU - Chung, Raymond T.
AU - Straub, Beate K.
AU - Schuppan, Detlef
AU - Ankavay, Maliki
AU - Cocquerel, Laurence
AU - Schaeffer, Evelyne
AU - Goossens, Nicolas
AU - Koh, Anna P.
AU - Mahajan, Milind
AU - Nair, Venugopalan D.
AU - Gunasekaran, Ganesh
AU - Schwartz, Myron E.
AU - Bardeesy, Nabeel
AU - Shalek, Alex K.
AU - Rozenblatt-Rosen, Orit
AU - Regev, Aviv
AU - Felli, Emanuele
AU - Pessaux, Patrick
AU - Tanabe, Kenneth K.
AU - Heikenwälder, Mathias
AU - Schuster, Catherine
AU - Pochet, Nathalie
AU - Zeisel, Mirjam B.
AU - Fuchs, Bryan C.
AU - Hoshida, Yujin
AU - Baumert, Thomas F.
N1 - Funding Information:
This work was supported by ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC1.0 and 2.0 IHUARC IHU201301187 and IHUARC2019 to T.F.B.), the European Union (ERC-AdG-2014-671231-HEPCIR to T.F.B. and Y.H., EU H2020-667273-HEPCAR to T.F.B. and M.H., and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to T.F.B. and M.B.Z), ANRS, Paris (2013/108 and ECTZ103701 to T.F.B), NIH (DK099558 to Y. H., and CA233794 to Y.H. and T. F. B; CA140861 to B.C.F.; and CA209940, R21CA209940, and R03AI131066 to N.P. and T.F.B.), Cancer Prevention and Research Institute of Texas (RR180016 to Y.H.), US Department of Defense (W81XWH-16-1-0363 to T.F.B. and Y.H.), the Irma T. Hirschl/Monique Weill-Caulier Trust (Y.H.), and the Foundation of the University of Strasbourg (HEPKIN to T. F. B. and Y. H.) and the Institut Universitaire de France (IUF; T.F.B.). M.H. is supported by an ERC CoG grant (HepatoMetaboPath) and EOS grant and by the Deutsche For-schungsgemeinschaft (DFG, German Research Foundation)—Project-ID 272983813— TRR 179, and Project-ID 314905040 SFB TR209. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and Inserm Plan Cancer and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program. We thank Prof. R. Bartens-chlager (University of Heidelberg, Germany) for providing plasmids for production of HCVcc Jc1 strains, Dr. F. Chisari (The Scripps Research Institute, La Jolla, CA) for the gift of Huh7.5.1 cells, Dr. A. Patel (MRC Virology Unit, Glasgow, UK) for E2-specific mAb AP33, Dr. J. Taylor (Fox Chase Cancer Center, Philadelphia, CA) for HDV expression plasmids, Dr. F. Habersetzer (Strasbourg University Hospitals) for patient samples for isolation of anti-HDV antibodies and infectious HBV, and Drs. Tscha-harganeh and Dr. Feng Zhang (Broad Institute of Harvard and MIT) for access to plasmids. We acknowledge the CRB (Centre de Ressources Biologiques-Biological Resource Centre), Strasbourg, France, for the management of patient-derived liver tissues. We thank M. Parnot (Inserm U1110, Strasbourg, France) and S. Prokosch (Heidelberg University, Germany) for excellent technical assistance, Drs. D. Guenot and D. Reita (EA 3430, University of Strasbourg, France) for their assistance with hypoxia treatment experiments, Drs. M. Jovanovic, C. Nusbaum, I. Tirosh (Broad Institute of MIT and Harvard), and Dr. S. L. Friedman (Mount Sinai Hospital) for helpful discussions. We thank Dr. S. Chasserot (Plateforme Imagerie In Vitro—NeuroPôle—Strasbourg, France) for support of confocal microscopy analyses. Finally, we thank Single-Cell Discoveries B.V. team (Utrecht, The Netherlands) for the scRNA-Seq service and advice, NanoString Technologies, Inc. (Seattle, WA, USA) for technical advice, and Synthego (Synthego Corporation, Menlo Park, California, USA) for THP1 HRH2 KO cell engineering. Some elements of the figures (Figs. 1a, 3h, 3j, 4a, 5b, 6b, and 8, and Supplementary Figs. 5a, 10a, and 15) have been created with PowerPoint and Servier Medical Art (authorization: https://creativecommons.org/licenses/by/3.0/fr/).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85115391823&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25468-9
DO - 10.1038/s41467-021-25468-9
M3 - Article
C2 - 34535664
AN - SCOPUS:85115391823
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5525
ER -