Metallothionein gene transfection reverses the phenotype of activated human hepatic stellate cells.

Metallothionein (MT) gene therapy leads to resolution of liver fibrosis in mouse model. The present study was undertaken to test the hypothesis that reversal of the phenotype of activated hepatic stellate cells (HSCs) contributes to the fibrinolysis effect of MT. Human HSC LX-2 cells were activated after they were cultured for 24 hours, as indicated by expression of α-smooth muscle actin (α-SMA) and collagen-I and depressed expression of collagenases. Transfection with a plasmid containing human MT-IIA gene in the activated HSCs effectively increased the protein level of MT. The expression of MT was accompanied by the reduction in protein levels of α-SMA and collagen-I and a decrease in their mRNA levels. Of importance, MT gene transfection resulted in upregulation of matrix metalloproteinases 1, 8, and 13, which are involved in the resolution of liver fibrosis. This study demonstrates that reversal of the phenotype of activated HSCs, particularly the upregulation of collagenases, is likely to be involved in the resolution of liver fibrosis observed in MT gene therapy.