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

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A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
Nature Communications ( IF 16.6 ) Pub Date : 2021-09-17 , DOI: 10.1038/s41467-021-25468-9
Emilie Crouchet _{1,

2} , Simonetta Bandiera _{1,

2} , Naoto Fujiwara ₃ , Shen Li ₄ , Hussein El Saghire _{1,

2} , Mirian Fernández-Vaquero _{5,

6} , Tobias Riedl _{5,

6} , Xiaochen Sun ₃ , Hadassa Hirschfield ₃ , Frank Jühling _{1,

2} , Shijia Zhu ₃ , Natascha Roehlen _{1,

2} , Clara Ponsolles _{1,

2} , Laura Heydmann _{1,

2} , Antonio Saviano _{1,

2,

7} , Tongqi Qian ₃ , Anu Venkatesh ₃ , Joachim Lupberger _{1,

2} , Eloi R Verrier _{1,

2} , Mozhdeh Sojoodi ₄ , Marine A Oudot _{1,

2} , François H T Duong _{1,

2,

8} , Ricard Masia ₉ , Lan Wei ₄ , Christine Thumann _{1,

2} , Sarah C Durand _{1,

2} , Victor González-Motos _{1,

2} , Danijela Heide ₅ , Jenny Hetzer ₅ , Shigeki Nakagawa ₃ , Atsushi Ono ₁₀ , Won-Min Song ₁₁ , Takaaki Higashi ₁₂ , Roberto Sanchez ₁₃ , Rosa S Kim ₁₄ , C Billie Bian ₁₁ , Karun Kiani _{15,

16} , Tom Croonenborghs _{15,

16,

17} , Aravind Subramanian ₁₅ , Raymond T Chung ₁₈ , Beate K Straub ₁₉ , Detlef Schuppan _{20,

21} , Maliki Ankavay ₂₂ , Laurence Cocquerel ₂₂ , Evelyne Schaeffer ₂₃ , Nicolas Goossens ₂₄ , Anna P Koh ₃ , Milind Mahajan ₁₁ , Venugopalan D Nair ₂₅ , Ganesh Gunasekaran ₂₆ , Myron E Schwartz ₂₆ , Nabeel Bardeesy ₂₇ , Alex K Shalek _{16,

28,

29} , Orit Rozenblatt-Rosen _{16,

30} , Aviv Regev _{16,

30,

31} , Emanuele Felli _{1,

2,

7} , Patrick Pessaux _{1,

2,

7} , Kenneth K Tanabe ₄ , Mathias Heikenwälder ₅ , Catherine Schuster _{1,

2} , Nathalie Pochet _{15,

16} , Mirjam B Zeisel _{1,

2,

32} , Bryan C Fuchs _{4,

33} , Yujin Hoshida ₃ , Thomas F Baumert _{1,

2,

7}

Affiliation

Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
Université de Strasbourg, Strasbourg, France.
Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
Department of Pharmacological Sciences and Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Department of Neurology, Harvard Medical School, Boston, MA, USA.
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
KU Leuven Technology Campus Geel, AdvISe, Geel, Belgium.
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Institute of Pathology, University Medicine, Johannes Gutenberg University, Mainz, Germany.
Institute for Translational Immunology and Research Center for Immunotherapy (FZI), Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
University of Lille, CNRS, Inserm, CHU Lille, Pasteur Institute of Lille, U1019-UMR 8204-CIIL- Center for Infection and Immunity of Lille, Lille, France.
CNRS UPR3572 Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC), Strasbourg, France.
Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland.
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Massachusetts General Hospital Cancer Center; Harvard Medical School, Cambridge St. CPZN 4216, Boston, MA, USA.
Institute for Medical Engineering Science & Department of Chemistry, MIT, Cambridge, MA, USA.
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Genentech, 1 DNA Way, South San Francisco, CA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), Lyon, France.
Ferring Pharmaceuticals Inc 4245 Sorrento Valley Blvd, San Diego, CA, USA.

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⁺, CLEC5A^high, MARCO^low 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.

中文翻译：

基于人类肝细胞的系统对临床预后肝脏特征进行建模以进行治疗发现

慢性肝病和肝细胞癌 (HCC) 是威胁生命的疾病，治疗选择有限。缺乏临床相关/易于处理的实验模型阻碍了治疗发现。在这里，我们开发了一个简单而强大的基于人类肝细胞的系统，该系统对预测长期肝病进展为 HCC 的临床预后肝脏特征 (PLS) 进行建模。使用 PLS 作为读数，然后在非酒精性脂肪性肝炎/纤维化/HCC 动物模型和患者衍生的肝球体中进行验证，我们确定了尼扎替丁，一种组胺受体 H2 (HRH2) 阻滞剂，用于治疗晚期肝病和 HCC 化学预防。此外，扰动研究与患者肝组织的单细胞 RNA-Seq 分析相结合，发现肝细胞和 HRH2 ⁺、 CLEC5A^高, MARCO作为潜在的尼扎替丁靶点的^{低肝巨噬细胞。}PLS 模型与患者组织的单细胞 RNA-Seq 相结合，能够发现治疗晚期肝病和癌症预防急需的靶点和疗法。

更新日期：2021-09-17

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