My laboratory studies the mechanisms of hepatic fibrosis. Our overall goal is to develop a model of fibrosis pathogenesis integrating cellular, soluble, and mechanical factors. The cells classically implicated in liver fibrosis are hepatic stellate cells, vitamin A-storing cells that undergo differentiation to fibrogenic myofibroblasts in the setting of chronic liver injury. The lab has studied the effects of TGF-β, the most important soluble mediator of fibrosis, on stellate cells and has shown that it plays a key role in stress fiber organization and contractility. We have also identified two additional myofibroblast precursor populations, portal fibroblasts and biliary epithelial cells undergoing EMT, that play an important role in biliary fibrosis and that are dependent on TGF-β for the myofibroblast phenotype. All of these cell types undergo myofibroblastic differentiation in culture as a function of the mechanical stiffness of the matrix. Animal models of liver fibrosis suggest that the same holds true in vivo – increased liver stiffness precedes and is required for myofibroblast differentiation. Ongoing work is focused on the role of mechanics at both the whole organ level and the level of the individual cells, and on the role of TGF-β in mediating mechanical changes.