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

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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.