Transplantation of urokinase‐type plasminogen activator gene‐modified bone marrow‐derived liver stem cells reduces liver fibrosis in rats

Abstract

Bone marrow-derived liver stem cells (BDLSCs) are very robust cells that can differentiate into liver epithelial cells. These stem cells are promising targets for gene therapy treatment of liver diseases. Liver fibrosis results from chronic liver damage characterized by an accumulation of extracellular matrix (ECM) and levels of urokinase-type plasminogen activator (uPA) play an important role in ECM degradation. In the present study, we investigated the therapeutic effects of uPA gene-modified BDLSC transplantation on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. BDLSCs were obtained from the bone marrow of cholestatic rats. These stem cells were selected and proliferated in medium containing 5% cholestatic serum. BDLSCs transfected with adenovirus-mediated human urokinase-plasminogen activator were transplanted into rats with CCl(4)-induced hepatic fibrosis. Liver function and the area of hepatic fibrosis were correlated with the development and prognosis of hepatic fibrosis. Hepatocyte-like colony-forming units were formed by bone marrow cells after 2 weeks in culture. In the uPA gene-modified BDLSC group, the areas of hepatic fibrosis were smaller and liver function was markedly ameliorated compared to controls. The expression of alpha-smooth muscle actin protein, transforming growth factor-beta1 protein and collagen types I and III mRNA were downregulated. By contrast, the levels of matrix metalloproteinases-2, -3 and -9 mRNA, hepatic growth factor mRNA and proliferating cell nuclear antigen protein increased. Transplantation of uPA gene-modified BDLSCs may suppress hepatic fibrosis and ameliorate liver function.