Mechanistic and therapeutic implications of PDGF-b activation during liver fibrogenesis

The role of platelet-derived growth factor (PDGF) family for the perpetuation of liver fibrogenesis and stellate cell activation is well documented. Increasing PDGF-b levels are observed in patients with severe liver fibrosis. We have recently demonstrated that forced expression of PDGF-b in hepatocytes results in spontaneous liver fibrosis, but the exact molecular mechanisms and signaling pathways remain unknown. The goal of this study was to dissect the role of PDGF-b by using whole transcriptomic time-course analysis to identify potential therapeutic targets for liver fibrosis. PDGF-b transgenic (Tg) and Alb-Cre-Ctl mice were investigated over a period of 32 weeks. Macroscopic and microscopic changes were monitored by IHC, RT-PCR and Western blotting. Time-dependent transcriptomic changes were examined using microarrays.PDFG-b transgenic animals developed spontaneous and severe liver fibrosis. Phenotypically, changes were accompanied by progressive accumulation of HSC and increased collagen deposit. Transcriptomic analysis revealed time-dependent activation of gene sets important for extracellular matrix remodeling, cell cycle as well as PDGF-b signaling and involved upregulation of known HSC markers (Thy–1) and key-fibrogenic molecules such as collagens, Timp2 and Ctgf in PDGF-b-Tg animals. Further, downregulation of Cebp-a and Ppar-a both associated with liver fibrogenesis was observed. Importantly, significant elevation of PDGF-b levels was also observed in human patients with cirrhosis and liver cancer.In conclusion, forced PDGF-b expression lead to spontaneous and progressive liver fibrosis in both human and rodents by upregulation of key fibrogenic molecules and inhibition of protective signaling such as PPAR-a and CEBP-a. Our results indicate the potential of modulating molecules embedded in PDGF-b signaling as an attractive anti-fibrogenic strategy for human liver fibrosis highlighting the translational significance of the PDGF-b transgenic model.

PDGF-b - fibrogenesis - hepatic stellate cells