Plasmin-mediated Proteolysis Is Required for Hepatocyte Growth Factor Activation during Liver Repair

Kumar Shanmukhappa,Ursula Matte,Jay L Degen,Jorge A Bezerra

doi:10.1074/jbc.m807313200

Abstract

The physiological relevance of the activation of hepatocyte growth factor (Hgf) by the plasminogen (Plg) system of proteases and its contribution to tissue repair are largely undefined. Here, we investigated whether the defective liver repair in mice lacking Plg is due to impaired activation of Hgf. Loss of Plg in vivo suppressed Hgf activation and signaling through its Met tyrosine kinase receptor. Without Plg, hepatocytes were unresponsive to Hgf-induced proliferation and migration, with a more pronounced impairment in hepatocyte movement within the hepatic environment. Most notably, circumventing the defect in proteolytic activation of Hgf by the downstream expression of an activated Met receptor corrected the functional deficits and improved liver repair in Plg-deficient mice. These findings support a fibrinolysis-unrelated role for Plg in modulating cell proliferation and migration by activation of Hgf.

Highlights

We previously reported that a genetically imposed loss of circulating Plg severely impairs clearance of necrotic cells and the repopulation of injured zones by newly formed cells but without compromising the general hepatic proliferative response [5]
Suppressed Activation of hepatocyte growth factor (Hgf) in Plgo Livers—We first determined whether Plg modulates Hgf activation by quantifying the expression of the ␣-heavy chain Hgf (␣Hgf), which is detected after Hgf activation, in livers of Plgϩ and Plgo mice at different time points after a single intraperitoneal dose of CCl4; mouse survival was similar in both genotypes after CCl4 administration, as reported previously [5]
These findings provided the first evidence that the loss of Plg limited Hgf activation in vivo and impeded Met signaling during the reparative response of the liver to an injury

Summary

Introduction

We previously reported that a genetically imposed loss of circulating Plg severely impairs clearance of necrotic cells and the repopulation of injured zones by newly formed cells but without compromising the general hepatic proliferative response [5]. To determine whether activation of Met corrects the defective repair induced by Plg deficiency, Ad-cyto-MetGFP or Ad-GFP was administered (1010 plaque-forming units/g of body weight) into the tail vein 2 days after administration of CCl4 to Plgo or Plgϩ mice.

Results

Conclusion