Intrahepatic gene expression profiles and alpha‐smooth muscle actin patterns in hepatitis C virus induced fibrosis†

Abstract

To gain insight into pathogenic mechanisms underlying fibrosis in hepatitis C virus (HCV)-mediated liver injury, we compared intrahepatic gene expression profiles in HCV-infected patients at different stages of fibrosis and ␣-smooth muscle actin (␣-SMA) staining patterns. We studied 21 liver biopsy specimens: 5 had no fibrosis (Ludwig-Batts stage 0); 10 had early portal or periportal fibrosis (stages 1 and 2); and 6, advanced fibrosis (stages 3 and 4). None of the patients had hepatocellular carcinoma. Transcriptional profiles were determined by high-density oligonucleotide microarrays. ANOVA identified 157 genes for which transcript abundance was associated with fibrosis stage. These defined three distinct hierarchical clusters of patients. Patients with predominantly stage 0 fibrosis had increased abundance of mRNAs linked to glycolipid metabolism. PDGF, a potent stellate cell mitogen, was also increased. Transcripts with increased abundance in stages 1 and 2 fibrosis were associated with oxidative stress, apoptosis, inflammation, proliferation, and matrix degradation, whereas transcripts increased in stages 3 and 4 were associated with fibrogenesis and cellular proliferation. Cells staining for ␣-SMA were detectable at all stages but infrequent in advanced fibrosis without active inflammation. A high frequency of such cells was associated with mRNAs linked to glycolipid metabolism. In conclusion, the presence of ␣-SMA-

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

“…While this approach cannot directly ascribe gene expression to stellate cells, in many cases their contribution to the pool of expressed mRNAs can be inferred, but must be validated using in situ methods or analysis of isolated cells. Nonetheless, at least six studies in humans (22,53,338,591,592,610) and one in rats (506) have explored this question, with interesting results. For example, one study of HCV-infected livers (591) identified mRNAs for the fibrosis-associated protein extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) and discoidin domain receptor-1 (CD167), which had not previously been identified in liver, prompting the need to explore these transcripts in isolated stellate cells.…”

“…Another study indicated that genes involved in matrix turnover and immune response may be critically associated with the transition from mild to moderate fibrosis (22), highlighting the key role of stellate cell behavior in this transition. Similarly, an analysis of human livers with HCV uncovered an abundance of transcripts associated with inflammation and matrix turnover in early fibrosis, whereas in advanced fibrosis genes associated with cellular proliferation predominated (338). Yet another study in whole liver of patients with HCV reported a predominance of transcription factors that are regulated by interferon (53).…”

Molecular Targeted Therapy for Hepatocellular Carcinoma: Present Status and Future Directions

“…18) In the early stage of chronic hepatitis, the expression of PDGF was upregulated, which suggests that PDGF is related to the development of fibrosis in chronic hepatitis. 19) Since HCC is a highly vascularized tumor, the targeting of well-known angiogenic factors, such as VEGF, FGF, and PDGF, is appealing for the molecular therapy of HCC.…”

Multiparameter Immune Profiling of Operational Tolerance in Liver Transplantation

“…The second category consists of pro-inflammatory genes exhibiting marked overexpression on HCV-positive recipients. Microarrays have been previously employed to analyze intrahepatic gene expression profiles in HCV infection following transplantation, revealing significant up-regulation of genes involved in oxidative stress, inflammation, T-cell activation, matrix degradation/fibrogenesis and apoptosis (28)(29)(30). However, the influence of both HCV infection and pharmacological IS on peripheral blood gene expression patterns had not been previously explored.…”