间充质干细胞（MSCs）治疗肝纤维化机制不明，旁分泌产生的细胞因子发挥重要作用。前期我们发现：①MSCs分泌的TSG-6是关键的抗肝纤维化因子；②芯片结果提示TSG-6可显著影响MMP12的表达；③MMP12抑制星状细胞活性；④清除体内巨噬细胞后小鼠肝损伤程度更重，且体内缺乏巨噬细胞时，TSG-6不能发挥治疗作用。由于巨噬细胞是MMP12的唯一来源，且参与调控肝纤维化。据此我们推测：TSG-6可能通过调控巨噬细胞影响MMP12表达，进而改善纤维化。然而TSG-6如何调控巨噬细胞？巨噬细胞如何影响MMP12表达？尚不明确。本课题拟从细胞水平上揭示TSG-6调控MMP12的信号途径，探索MMP12对星状细胞增殖凋亡及巨噬细胞分泌炎症因子的影响；从动物模型上明确MMP12在肝纤维化发生发展及治疗中的作用。研究结果有助于阐明TSG-6治疗肝纤维化的分子机理，为肝纤维化细胞因子替代治疗提供新的思路。

The mechanism of mesenchymal stem cells (MSCs) therapy for liver fibrosis is far from being understood, and cytokines produced by MSCs paracrine play an important role. In the previous study, we found that TSG-6 is a major antifibrotic cytokine of MSCs. In addition, TSG-6 could significantly affect the expression of MMP12. MMP12 could suppress hepatic stellate cells activation. Furthermore, the severity of liver damage was more serious after the removal of macrophages in vivo, and TSG-6 was inefficacy if there no macrophages in vivo. Since macrophages are the only source of MMP12 and they are the key regulator of liver fibrosis. Thus, we hypothesized that TSG-6 secreted by MSCs may affect MMP12 expression by regulating macrophages, thereby improving fibrosis. However, the mechanism by which TSG-6 regulates macrophages and macrophages regulate MMP12 remains unclear. We are going to investigate the transduction pathway of TSG-6 regulating MMP12 and explore the effect of MMP12 on proliferation and apoptosis of stellate cells and secretion of inflammatory cytokines by macrophages. The role of MMP12 in the development and treatment of liver fibrosis was further clarified. This study may help to clarify the molecular mechanism of TSG-6 therapy for liver fibrosis and provide new ideas for cytokine replacement therapy of liver fibrosis.