活化的肌成纤维细胞（myofibroblasts, MF）在肝纤维化进程中发挥重要作用,骨髓来源的纤维细胞可以活化为MF参与纤维化进程，其在体内外不同环境中具有多相细胞分化潜能，但在受损肝脏中的分化尚未得到证实。前期研究发现：抑制纤维细胞分化的血清淀粉样物质P（SAP），具有明显的抗肝纤维化作用,提示纤维细胞在受损肝脏中可能发挥重要促纤维化作用，与其具有的多相分化潜能相关。本课题拟利用四氯化碳及胆管结扎诱导的小鼠肝纤维化模型，首先在肝纤维化全程及纤维细胞向肝脏募集高峰阶段条件性敲除骨髓来源的纤维细胞，观察肝纤维化改善情况；其次在纤维化起始阶段及已发生阶段利用化合物SAP进行干预，同时明确纤维化的改善与纤维细胞向肝脏募集相关；最后通过细胞示踪方法，研究肝脏损伤过程中骨髓来源的纤维细胞在肝脏中分化为Kupffer细胞和树突状细胞的潜能，为全面了解纤维细胞在肝纤维化进展过程中的作用提供实验依据。

Activation and proliferation of hepatic myofibroblasts are required for the development of liver fibrosis. One of the most exciting new concepts in fibrosis is the potential contribution of Bone Marrow (BM) derived fibrocytes to liver fibrosis, that are CD45 and Type I collagen expressing cells. It has been confirmed that BM-derived fibrocytes contribute 4-6% of all collagen expressing cells (myofibroblasts) in the fibrotic liver. Fibrocytes can differentiate into multiple cell types under different conditions, but the differentiation of recruited BM-derived fibrocytes in injuried liver remains unclear. Our previous studies found that Serum Amyloid P (SAP), which is the natural inhibitor of fibrocytes differentiation, could significantly attenuate liver fibrosis by 45%, indicating the important role of fibrocytes in the liver fibrogenesis. Accordingly, we hyposithesied that fibrocytes are mobilized from bone marrow to the liver in response to injury to generate multiple cell types that stimulate fibrosis, and that targeting fibrocyes in the setting of liver fibrosis will improve fibrosis. In this study, we will first use inducible genetic ablation of fibrocytes to determine the role of fibrocytes in experimental hepatic fibrosis. Ablation of fibrocytes throughout the duration or at the onset of liver injury was carried out in carbon tetrocloride (CCl4) and bile duct ligation (BDL) induced liver fibrosis. Secondly, we will use pharmacological inhibition of fibrocytes-SAP to determine the important role of fibrocytes in the pathogenesis of liver fibrosis. SAP will be injected into both CCl4 and BDL induced liver fibrosis mice model and the recruitment of fibrocytes will be observed in CCl4-treated Col-GFP→wt mice by GFP expression. The inhibition of fibrocytes recruitment will be observed by GFP expression. Finally, to gain greater insight into mechanisms by which a relatively small number of fibrocytes can substantially contribute to fibrosis, we develop a cell fate mapping approach to determine fibrocyte functions. The differentiation of fibrocytes into myofibroblasts, macrophages, and dendritic cells will be detected, and their characteristics will be compared with that of resident macrophages and dendritic cells in liver. The results of our studies will give greater insight into mechanisms underlying the role of fibrocytes in liver fibrosis and validate fibrocytes as a potential therapeutic target.