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

骨髓来源的循环纤维细胞（CF）参与了几个器官的纤维化。我们证明了CF到损伤的肝脏中的募集及其分化为促纤维化的肌成纤维细胞。此外，已知在肝纤维化的情况下，来自骨髓的细胞积极参与肝再生。在肝纤维化过程中，CF被证明分泌基质金属蛋白酶（MMPs）。从而减少细胞外基质的量。然而，它是绝对未知的定量影响CF在肝纤维化以及在肝再生。此外，评估CF消融是否代表肝纤维化的治疗选择也是一个非常重要的问题。在我们的项目中，我们计划在不同的肝纤维化模型中描述CF对肝纤维化发生和再生的重要性。此外，我们确定任何治疗潜力的调制CF。因此，将GFP转基因小鼠（携带单纯疱疹病毒胸苷激酶/更昔洛韦，受I型胶原启动子控制）的骨髓静脉内移植到经致死照射的自发性（Abcb 4-/-）或毒性诱导（TAA）肝纤维化小鼠体内。更昔洛韦选择性消融CF的体内和体外治疗效果有待进一步研究。在第二种更多的翻译方法中，我们打算探索IL-4和IL-13敲除对CF生物学的影响。除了分析CF消融对肝脏分级和分期的直接影响外，计划检查已知参与纤维发生的旁分泌信号传导途径（趋化因子、细胞因子、5-LO-白三烯、生长因子）。以上小鼠模型均在本实验室建立。我们的研究结果将为肝纤维化的发生、诊断、预防和治疗提供细胞生物学原理。

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.