Cellular and molecular mechanisms of the improvement of non-alcoholic steatohepatitis by mesenchymal stem cells in the immune-deficient mouse

人骨髓间充质干细胞(MSC)可改善免疫缺陷小鼠的非酒精性脂肪性肝炎(NASH)，改善脂质代谢、肝纤维化和炎症反应，并促进肝再生。这意味着MSC具有代谢、抗纤维化、抗炎和促增殖作用，蛋白质组学分析证实了这一点。该项目的目标是在分子和细胞水平上揭示MSC的作用模式。这将通过研究MSC对NASH中碳水化合物和脂肪代谢的转录调节、作为纤维化主要介导者的肝星状细胞的调节以及作为最可能触发肝脏炎症反应的天然免疫(Kupffer细胞和树突状细胞、巨噬细胞、粒细胞、补体系统)的调节来实现。对这些机制的了解开启了长远的视野，将人类骨髓间充质干细胞应用于NASH所致的肝硬变的治疗，从而确立干细胞移植作为治疗终末期慢性肝病的一种治疗选择，作为器官移植的替代方案。对MSC作用的分子成分的阐明也将有助于开发药物治疗方法，最终使NASH和由此引起的慢性肝病的非细胞治疗成为可能。

Human mesenchymal stem cells (MSC) improved the non-alcoholic steatohepatitis (NASH) in an immuno-deficient mouse model by the amelioration of lipid metabolism, fibrosis and inflammation as well as by the stimulation of liver regeneration. This implies a metabolic, anti-fibrotic and anti-inflammatory as well as pro-proliferative action of the MSC, as was verified by proteomics analyses. It is the aim of the project to unravel the mode of action of the MSC on both the molecular and the cellular level. This will be achieved by investigating the impact of the MSC on transcriptional regulation of carbohydrate and lipid metabolism, the regulation of hepatic stellate cells as the main mediators of fibrosis as well as the regulation of innate immunity as the most likely trigger of the hepatic inflammatory reaction (Kupffer- and dendritic cells, macrophages, granulocytes, complement system) in NASH. The knowledge of these mechanisms opens the long-term perspective, to apply human MSC for the therapy of cirrhosis as the consequence of NASH and thus to establish stem cell transplantation as a therapy option to treat end-stage chronic liver diseases as an alternative to organ transplantation. The elucidation of the molecular components of MSC action will also allow for the development of pharmacological therapeutic approaches, which eventually enables the cell-independent treatment of NASH and resulting chronic liver diseases.