TGF-beta up-regulates serum response factor in activated hepatic stellate cells.

In differentiated smooth muscle cells (SMC) the regulation of SMC marker genes (e.g. alpha-smooth muscle actin) is mainly conducted by the serum response factor (SRF) and accessory co-factors like myocardin. A number of SMC markers are also expressed in activated hepatic stellate cells which are the main cellular effectors in liver fibrogenesis. In the present study we found that during cellular activation and transdifferentiation the SRF transcription factor is up-regulated by transforming growth factor-beta, accumulated in the nucleus, and exhibited increased DNA-binding activity. These observations were accompanied by a forced expression of the SRF co-activator myocardin. Specific targeting of SRF by small interference RNA resulted in diminished contents of alpha-smooth muscle actin. Therefore, we conclude that hepatic stellate cells retain differentiation capacity to evolve characteristics that are typical for cells of the cardiac and smooth muscle lineages.