Importance of circulating fibrocytes for hepatic fibrogenesis, fibrolysis and regeneration.

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Bone-marrow-derived circulating fibrocytes (CF) are implicated in fibrogenesis of several organs. We demonstrated the recruitment of CF into the injured liver and their differentiation into pro-fibrogenic myofibroblasts. In addition it is known that cells from the bone marrow are actively involved in liver regeneration in the case of liver fibrosis. During hepatic fibrolysis CF were shown to secret Matrix Metalloproteinases (MMPs). Thus reducing the amount of extracellular matrix. However, it is absolutely unknown of what quantitatively impact CF are in hepatic fibrogenesis as well as in hepatic regeneration. In addition it is of burning interest to evaluate whether ablation of CF represents a therapeutic option for liver fibrosis. With our project we plan to characterize the importance of CF for hepatic fibrogenesis and regeneration in different models of heaptic fibrosis. Furthermore, we determine any therapeutical potential of modulating CF. For this reason bone marrow of GFP transgenic mice (bearing the herpes simplex virus thymidin kinase / Ganciclovir under control of colla-gen type I promotor) will be transplanted i.v. into letally irradiated mice with spontanous (Abcb4-/-) or toxically induced (TAA) hepatic fibrosis. In vivo und in vitro the selective CF ab-lation by Ganciclovir will be explored with regard to its therapeutical capacity. In a second more translational approach we intend to explore the affect of IL-4 and IL-13 knockout on CF biology. Beyond the analysis of the direct effects of CF ablation on liver grading and staging the examination of parakrine signalling pathways are planned known to be involved in fibro-genesis (chemokines, cytokines, 5-LO-leukotrienes, growth factors). All mouse models men-tioned are established in our lab. Our results will provide a contribution to the cell biological principles of development, diagnosis, prophylaxis and managment of hepatic fibrogenesis.