MODULATION OF THE PLASMINOGEN-ACTIVATOR PLASMIN SYSTEM IN RAT-LIVER REGENERATING BY RECRUITMENT OF OVAL CELLS

The proteolytic cascade involving plasminogen activators and plasmin a ppears to have an important function in tissue regeneration. We have i nvestigated the expression and cellular localization of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator receptor (uPAR), and plasminogen activator inhibitor-1 (PAl-1) as well as plasminogen activation in ra t liver regeneration by recruitment of progenitor (oval) cells. Using a model in which surgical partial hepatectomy is combined with feeding of 2-acetylaminofluorene (2-AAF) to induce liver regeneration by prol iferation and differentiation of oval cells, expression of uPA, uPAR, and PAl-1 was detected by immunohistochemistry mainly in the duct-like formations of expanding oval cells. Plasminogen activation, as assess ed by direct zymography on frozen liver sections, was located over the expanding oval cell populations but not over mature hepatocytes. Plas minogen activation was not detected in control liver. Expression of uP A, uPAR, and PAl-1, as assessed by immunohistochemical and Northern bl ot analyses, was also observed, when cells located in and in close pro ximity to the bile epithelial structures were activated to enter DNA-s ynthesis in response to 2-AAF, and after in vivo infusion of various g rowth factors. Given the physiologic function of plasminogen activatio n in fibrinolysis, and plasminogen activators in activation of latent growth factors, the selective expression of the plasminogen activator/ plasmin proteolytic cascade in oval cells expanding during liver regen eration in response to the combination of 2-AAF and partial hepatectom y, may confer a proliferative advantage to these cell populations in a n extracellular matrix containing both fibrin and latent growth factor s.