Development of Therapentic Method to Promote Liver Regeneration by Modulating the Activin-Follistatin System

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Activin A is an autocrine growth inhibitor of hepatocytes. When hepatocytes were stimulated by growth factors, activin A is synthesized in the middle to late G_1 phase and inhibits initiation of DNA synthesis. Reversal of the inhibitory effect of activin A by adding follitatin, an activin-binding protein, augments DNA synthesis. Activin A is expressed in the remnant liver after partial hepatectomy. When follistatin was infused into the rat portal vein immediately after the 70% hepatectomy, liver regeneration was accelerated. Initiation of DNA synthesis was observed 6 hrs earlier than in control rats. The remnant liver weight and liver regeneration rate were significantly greater in follistatin-treated rats. When ^<125>I-follistatin administered intravenously, about 10% of the ^<125>I-follistatin was accumulated in the liver. The amount of follistatin in the liver remained elevated for up to 72 hrs but decreased thereafter. A booster shot of follistatin at 72 hrs maintained the intrahepatic follistatin at the high level for up to 120 hrs. When follistatin was infused intravenously after 70% hepatectomy followed by a booster shot at 72 hrs, the liver regeneration, as assese by the DNA content, remnant liver weight and liver regeneration rate, was significantly augmented. These results indicate the effectiveness of follistatin in promoting liver regeneration after partial hepatectomy.