A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
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 p...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
17 September 2021
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| In: |
Nature Communications
Year: 2021, Volume: 12, Pages: 1-19 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-25468-9 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-021-25468-9 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-021-25468-9 
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| Author Notes: | 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 & Thomas F. Baumert |
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| 520 | |a 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. | ||
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| 650 | 4 | |a Computational biology and bioinformatics | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a Liver diseases | |
| 650 | 4 | |a Mechanisms of disease | |
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