Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice

• Published in: Journal of hepatology 2006-09, Vol.45 (3), p.419-428
• Main Authors: Czochra, Piotr, Klopcic, Borut, Meyer, Erik, Herkel, Johannes, Garcia-Lazaro, Jose Francisco, Thieringer, Florian, Schirmacher, Peter, Biesterfeld, Stefan, Galle, Peter R., Lohse, Ansgar W., Kanzler, Stephan
• Format: Article
• Language: English
• Subjects: Albumin promoter; Animals; Biological and medical sciences; Carbon tetrachloride; Cell Differentiation - genetics; Cell Proliferation; Cells, Cultured; Extracellular Matrix - metabolism; Fibroblasts - metabolism; Fibroblasts - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - genetics; Hepatic stellate cells; Hepatocytes - metabolism; Hepatocytes - pathology; Integrases - genetics; Integrases - metabolism; Liver - cytology; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver fibrosis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Transgenic; Other diseases. Semiology; PDGF-B; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - metabolism; TGF-β; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transgenic mice
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2006.04.010

In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice. Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/loxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured. PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-β expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4–6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-β expression was unchanged. We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-β1, suggesting a TGF-β-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.