The PDGF system and its antagonists in liver fibrosis

Abstract

Platelet derived growth factor (PDGF) signaling plays an important role in activated hepatic stellate cells and portal fibroblast proliferation, chemotaxis, migration and cell survival. PDGF receptors and ligands are upregulated in experimental liver fibrotic models as well as in human liver fibrotic diseases. Blocking of PDGF signaling ameliorates experimental liver fibrogenesis. The plurality of molecular and cellular activities of PDGF and its involvement in initiation, progression and resolution of hepatic fibrogenesis offers an infinite number of therapeutic possibilities. These include the application of therapeutic antibodies (e.g. AbyD3263, MOR8457) which specifically sequester individual PDGF isoforms or the inhibition of PDGF isoforms by synthetic aptamers. In particular, the isolation of innovative slow off-rate modified aptamers (e.g., SOMAmer SL1 and SL5) that carry functional groups absent in natural nucleic acids by the Systematic Evolution of Ligands by EXponential (SELEX) enrichment technique offers the possibility to design high affinity aptamers that target PDGF isoforms for clinical purposes. Dominant-negative soluble PDGF receptors are also effective in attenuation of hepatic stellate cell proliferation and hepatic fibrogenesis. Moreover, some multikinase inhibitors targeting PDGF signaling have been intensively tested during the last decade and are on the way into advanced preclinical studies and clinical trials. This narrative review aims to gauge the recent progression of research into PDGF systems and liver fibrosis.