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 C-related early-stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC) (n=82, prognostic index validation set). We then examined the association between hepatic stellate cell signature expression and decompensation, 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 death, decompensation, progression of Child–Pugh class and HCC incidence in a retrospective–prospective cohort of patients with hepatitis C cirrhosis. In the prognostic index derivation cohort (n=216), 66 (31%) died, 71 (34%) developed hepatic decompensation, 66 (31%) experienced progression of Child–Pugh class and 65 (30%) developed HCC. In the prognostic index validation cohort (n=82), 32 (39%) died and 65 (79%) developed tumour recurrence.
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 to 0.74) was improved by adding the hepatic stellate cell signature (c-index: 0.70, 95% CI 0.62 to 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 (c-index: 0.62, 95% CI 0.51 to 0.72). For other clinical outcomes examined, the prognostic index was associated with decompensation (c-index: 0.62, 95% CI 0.55 to 0.69), HCC (c-index: 0.63, 95% CI 0.56 to 0.71) and progression of Child–Pugh class (c-index: 0.70, 95% CI 0.63 to 0.78) in the derivation set, and HCC recurrence (c-index: 0.54, 95% CI 0.46 to 0.62) in the validation set.
Conclusions 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 patients with HCV cirrhosis or postresection HCC with poor prognosis.
- LIVER CIRRHOSIS
- HEPATIC FIBROSIS
- HEPATIC STELLATE CELL
- LIVER FAILURE