Study on the gene therapy of soluble-HB-EGF gene to accelerate liver regeneration.

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We have reported that heparin-binding EGF-like growth factor (HB-EGF) is a potent mitogen of hepatocytes in vitro. The level of HB-EGF mRNA in regenerating rat liver creases rapidly after a partial hepatectomy. In vitro study showed that HB-EGF induces the expression of HGF and TGF-alpha in non-parenchymal cells and hepatocytes, respectively. To clarify the role of soluble-HB-EGF, we studied the effect of an inhibitor which inhibits the post-tanslational processing from a membrane-bind form of HB-EGF to a soluble form, using HB-EGF transgenic mouse. The inhibitor decreased the labeling index of hepatocyte, indicating that soluble-HB-EGF is important in liver regeneration. We also investigated the effect of administration of soluble-HB-EGF to mice on proliferation of hepatocyte in vivo. Recombinant soluble-HB-EGF was administered intravenously to the normal mice for 4 times at 2h-interval. The labeling index is 300-fold higher in HB-EGF administered mice than that of controls. In vivo administration of HB-EGF activated NF-kB and STAT-3 in the liver. The induction of HGF was observed in HB-EGF-administered mice liver. To develop gene therapy of soluble-HB-EGF using HVJ-liposome method, we administered the HVJ-liposome to mouse intravenously. No serious adverse effect was observed by the administration. Injection of expression plasmid containing soluble-HB-EGF gene in HVJ-liposome in the *uscle of mouse increased the plasma levels of HB-EGF.These results indicated that introduction of soluble HB-EGF gene using HVJ-liposome method could be a candidate for new approach to accelerate the liver regeneration