A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
抄録
<jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup>, CLEC5A<jats:sup>high</jats:sup>, MARCO<jats:sup>low</jats:sup> 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.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 12 (1), 5525-, 2021-09-17
Springer Science and Business Media LLC