Hepatocyte Growth Factor is a multifunctional cytokine with mitogenic motogenic and morphogenic effects on many organs and cell types. Liver, however, is the organ whose development is predominantly affected in mice with gene knockouts for either HGF or its receptor (Met). In addition, HGF levels rise in the plasma during liver regeneration but not in that of other organs. The main aim of this application is to determine his HGF essential for liver regeneration and embryonic development and how is it brought to where it is needed by release from matrix, new synthesis and activation. We will examine the pathways leading to HGF release from liver after PHx. Evidence is presented that an orchestrated cascade of events starting from the urokinase receptor (uPAR) leads to simultaneous matrix degradation and HGF release and activation. Chronology of receptor activation following partial hepatectomy suggests that activation of other receptors precedes activation of Met. We will focus on the immediate early extracellular events that trigger the subsequent cascade of events leading to regeneration. We will use a newly developed in our lab culture system where parenchymal hepatocytes can expand as undifferentiated clones and undergo phenotypic transition to either mature hepatocytes or ductular hepatocytes. In these cultures of hepatoblasts, HGF induces the ductular phenotype. Ductular transformation of hepatocytes occurs transiently during embryology and during the late stages of fulminant hepatitis. Based on our findings will explore the hypothesis that formation of the ductular hepatocyte phenotype is under control of HGF and may correlate with the appearance of new transcription factors. Given the critical dependence of embryonic liver on this ductular transformation as well as the impact of the ductular transformation of hepatocytes to the lethality of fulminant hepatitis, these studies will examine the role of HGF in two critical stages at the beginning and (sometimes) the end of life. The role of HGF in hepatic neoplasia remains puzzling. Exogenously administered HGF inhibits proliferation of early hepatocellular carcinomas. Neoplastic development in HGF transgenics targeted to liver is far less than TGFalpha. We show that forced expression of HGF may accelerate growth in hepatoblasts. We will study growth and differentiation properties in culture and in transplantation of hepatoblasts /hepatocytes with forced expression of HGF. Following recent results in our lab, we will also pursue studies to examine the possibility that the effect of exogenous HGF on hepatic neoplasia may be stimulatory or inhibitory based on aberrant phosphorylation of Met induced by insulin or transferrin receptors.
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