Study on gene therapy for liver regeneration. -Effect of gene transduction of soluble HB-EGF and soluble TGF-β type II receptor on liver regeneration-

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Acceleration of liver regeneration is important for the treatment of hepatic failure. We have reported that HB-EGF is a potent mitogen of hepatocyte and plays an important role in liver regeneratian. On the other hands, TGF-β, a growth inhibitory factor stimulates apoptosis of hepatocyte and inhibits liver regeneration.In this study, we demonstrated that NF-kB is activated in hepatic non-parenchymal cells after partial hepatectomy and stimulates the expression of HB-EGF gene. We also indicated that soluble form of HB-EGF is essential for liver regeneration using HB-EGF transgenic mice.To develop the new methods for acceleration the liver regeneration, dual introduction of soluble HB-EGF gene and soluble TGF-βtype II receptor that blocks the action of TGF-β is investigated. We developed the expression plasmid containing soluble TGF-βtype II receptor cDNA attached with human immunoglobulin Fc region or soluble HB-EGF cDNA. Both genes were introduced into mice skeletal muscle using in vivo electroporation methods. The plasma concentration of soluble HB-EGF and soluble TGF-β type II receptor were measured with newly developed ELISA systems. Pretreatment with hyaluronidase increased the expression levels and obtains 6-fold higher concentrations of soluble HB-EGF or soluble TGF-βtype II receptor.Our results give a basis for development of the gene therapy to accelerate the liver regeneration.