Objective-We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells, and assessed the prognostic capability of their expression in cirrhosis.Design-We defined a hepatic stellate cell gene signature by comparing stellate, immune, and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective-prospective cohort of hepatitis Crelated early-stage cirrhosis (prognostic index derivation set), and validated in an independent retrospective cohort of post-resection HCC patients (n=82, prognostic index validation set). We then examined association between hepatic stellate cell signature expression and decompensation, hepatocellular carcinoma (HCC) incidence, and progression of Child-Pugh class as additional outcomes in the prognostic index derivation set, and HCC recurrence as an additional outcome in the validation set. We tested whether hepatic stellate cell signature expression is predictive of Results-The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors, and correlates with the extent of fibrosis in human, mouse, and rat datasets. The hepatic stellate cell signature contains several cell surface genes previously established as stellate cell-specific, as well as PCDH7, a novel protocadherin stellate cell surface marker. Importantly, association of clinical prognostic variables with overall survival (c-index: 0.66, 95% CI: 0.59-0.74) was improved by adding the hepatic stellate cell signature (cindex: 0.70, 95%CI: 0.62-0.78); we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival Conclusion-This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting, and isolation. Hepatic stellate cell signature expression may identify HCV cirrhosis or post resection HCC patients with poor prognosis.

With the novel risk scores, we can estimate the chance of HCC development more exactly and practically. This approach can be used for HCC screening in CHC patients achieving SVR.