The role of proteolytic system on the liver regeneration : The analysis of gene deficient mice with transplantation of bone morrow

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The liver regeneration after injury is regulated by variety of growth factors and cytokines. Release of these growth factors is deeply related to degradation of extracellular matrix (ECM). This ECM degradation is regulated by the activation of plasminogen (Plg) and matrix metalloproteinase (MMP) systems. The liver regenerations in knockout mice (-/-) for fibrinolytic factors were examined by using CCl_4 injection model. The ability of liver regeneration was significantly increased in the α_2-antiplasmin (α_2-AP) -/- as compared to the wild-type mice (WT), but was significantly decreased in the Plg-/-, or Plg-/-. α_2-AP-/-. Plg activator activity in the plasma and liver tissue extract after liver injury showed similar increase in all genotype mice. On the other hand, the proteolytic activity in liver tissue extract from Plg-/- after liver injury was lower than that α_2-AP-/- and WT. These results suggest that the fibrinolytic system playes an important role in the hepatic repair. Furthe … More r, we analyzed the relationship between the liver regeneration and fibrinolytic system by using the hepatocytes isolated from mouse liver. The proliferation ability of the hepatocytes isolated from mice without CCl_4 injection showed similar in all genotype mice. On the other hand, the proliferation ability of the hepatocytes from mice of 5 days after CCl_4 injection was significantly increased in the α_2-AP-/- as compared to the WT but was decreased in the Plg-/-. The hepatocytes isolated from all genotype mice similarly bound to the immobilized Plg. The activation of Plg was significantly increased in the presence of mouse hepatocytes. The plasmin inhibition by α_2-AP in the presence of mouse hepatocytes was weaker than that in the absence of mouse hepatocytes. On the other hand, The role of proteolytic system on the liver regeneration by the analysis of gene deficient mice with transplantation of bone morrow. Replacement of hepatocyte in Plg-/- mice with Plg+/+ bone marrow successfully restored the regeneration response after CCl_4 injure. These results indicate that the fibrinolytic system on the surfaces of mouse hepatocytes plays important roles in liver regeneration. Less