A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.
Nat Commun
; 12(1): 5525, 2021 09 17.
Article
in En
| MEDLINE
| ID: mdl-34535664
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Health context:
2_ODS3
Database:
MEDLINE
Main subject:
Drug Discovery
/
Liver
/
Models, Biological
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Language:
En
Journal:
Nat Commun
Year:
2021
Document type:
Article