Catherine Schuster

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

Publisher: Springer Science and Business Media LLC

Date: 17-09-2021

DOI: 10.1038/S41467-021-25468-9

Abstract: Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models h ers 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.

Université De Strasbourg, Inserm U1110/Inserm

Location: France

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Université De Strasbourg

Location: France

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