Emerging insights into Transforming growth factor   Smad signal in hepatic fibrogenesis

rrespective of initial stimuli, increased production of type I collagen is a common hallmark of fibrotic diseases in various organs including the liver. A dynamic balance between the production and degradation of collagen is seen, which is rigorously controlled by several growth factors and cytokines. Of these, transforming growth factor b (TGFb) is the most potent factor in stimulating type I collagen gene transcription. It also regulates expression of matrix metalloproteinases and their inhibitors, and modulates inflammatory reactions by influencing T cell functions. Therefore, TGFb is considered to be the major factor accelerating liver fibrosis. Identification and characterisation of Smad proteins, intracellular mediators of the signal transduction of TGFb, have led to a better understanding of the precise mechanisms of TGFb functions from the viewpoint of its intracellular signalling pathway and crosstalk with other factors. Several studies have focused on the suppression of TGFb activation and intervention of the TGFb/Smad signalling pathways to treat liver fibrosis. However, as generalised blockade of TGFb activity may result in the promotion of carcinogenesis and excessive immune reactions, much attention has to be paid to selective intervention of the TGFb/ Smad signal specifically in collagen-producing cells in the fibrotic tissue. TGFb also affects the growth and differentiation of stem and progenitor cells. From this point of view, a new concept of the treatment for liver fibrosis may arise from the discipline of stem cell biology by modulating TGFb and Smad signalling in stem/progenitor cells.