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

间充质干细胞改善免疫缺陷小鼠非酒精性脂肪性肝炎的细胞和分子机制

• 批准号: 280809505
• 负责人: Professor Dr. Bruno Christ
• 金额: --
• 依托单位: Forschungslaboratorien der Chirurgischen Kliniken I und II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280809505?language=en
• 关键词: Cellular; molecular; mechanisms; improvement; non

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.

人间充质干细胞（MSC）通过改善脂质代谢、纤维化和炎症以及刺激肝再生来改善免疫缺陷小鼠模型中的非酒精性脂肪性肝炎（NASH）。这意味着MSC的代谢、抗纤维化和抗炎以及促增殖作用，如通过蛋白质组学分析所证实的。该项目的目的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对碳水化合物和脂质代谢的转录调节、作为纤维化主要介质的肝星状细胞的调节以及作为NASH中肝脏炎症反应（枯否细胞和树突状细胞、巨噬细胞、粒细胞、补体系统）的最可能触发物的先天免疫的调节的影响来实现。这些机制的知识打开了长期的前景，应用人MSC治疗NASH导致的肝硬化，从而建立干细胞移植作为治疗终末期慢性肝病的治疗选择，作为器官移植的替代方案。MSC作用的分子组分的阐明也将允许开发药理学治疗方法，其最终能够实现NASH和由此产生的慢性肝病的细胞非依赖性治疗。

项目成果

Mesenchymal stromal cells may promote lipid utilization via increment of mitochondria biogenesis in targeted hepatocytes

间充质基质细胞可能通过增加目标肝细胞中的线粒体生物发生来促进脂质利用

• DOI: 10.1055/s-0039-3402133
• 发表时间: 2020
• 期刊: Zeitschrift für Gastroenterologie
• 作者: Hsu MJ;Christ M;Christ B
• 通讯作者: Christ B

Immune-Deficient Pfp/Rag2−/− Mice Featured Higher Adipose Tissue Mass and Liver Lipid Accumulation with Growing Age than Wildtype C57BL/6N Mice

与野生型 C57BL/6N 小鼠相比，免疫缺陷 Pfp/Rag2â/â 小鼠随着年龄的增长，脂肪组织质量和肝脏脂质积累更高

• DOI: 10.3390/cells8080775
• 发表时间: 2019
• 期刊: Cells
• 影响因子: 6
• 作者: Winkler S;Hempel M;Hsu MJ;Gericke M;Kühne H;Brückner S;Erler S;Burkhardt R;Christ B
• 通讯作者: Christ B

Metabolic fingerprint of an immunodeficient NASH mouse model and impact after stem cell therapy

免疫缺陷 NASH 小鼠模型的代谢指纹及干细胞治疗后的影响

• 发表时间: 2017
• 期刊: Journal of Hepatology
• 影响因子: 25.7
• 作者: Winkler S;Kalkhof S;Brückner S;Hempel H;Baumann S;von Bergen M;Christ B
• 通讯作者: Christ B

Die Peroxisomen als Zielstruktur für die Stammzelltherapie bei MCD-Diät induzierter NASH in einem immundefizienten Mausmodell

过氧化物酶体作为干细胞治疗免疫缺陷小鼠模型 MCD 饮食诱导 NASH 的靶结构

• DOI: 10.1055/s-0037-1605071
• 发表时间: 2017
• 期刊: Zeitschrift für Gastroenterologie
• 作者: Winkler S;Kalkhof S;Brückner S;Hempel M;Bosse I;Baumann S;von Bergen M;Christ B
• 通讯作者: Christ B

Metabolische Wirkungen mesenchymaler Stromalzellen in der nicht-alkoholischen Steatohepatitis

间充质基质细胞在非酒精性脂肪性肝炎中的代谢作用

• DOI: 10.1055/s-0038-1677191
• 发表时间: 2019
• 期刊: Zeitschrift für Gastroenterologie
• 作者: Winkler S;Kratochvil I;Hempel M;Kühne H;Kalkhof S;Baumann S;Schubert K;von Bergen M;Christ B
• 通讯作者: Christ B