Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH
Open Access
- 13 September 2020
- journal article
- research article
- Published by MDPI AG in Biomedicines
- Vol. 8 (9), 350
- https://doi.org/10.3390/biomedicines8090350
Abstract
Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (CH109/22-2)
This publication has 101 references indexed in Scilit:
- clusterProfiler: an R Package for Comparing Biological Themes Among Gene ClustersOMICS: A Journal of Integrative Biology, 2012
- Peroxisomal and Microsomal Lipid Pathways Associated with Resistance to Hepatic Steatosis and Reduced Pro-inflammatory StateJournal of Biological Chemistry, 2010
- Diversity in Antioxidant Response Enzymes in Progressive Stages of Human Nonalcoholic Fatty Liver DiseasePublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2010
- Optimization of parameters for coverage of low molecular weight proteinsAnalytical and Bioanalytical Chemistry, 2010
- Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic SteatohepatitisJournal of Biological Chemistry, 2010
- Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRtNature Protocols, 2009
- Autophagy regulates lipid metabolismNature, 2009
- WGCNA: an R package for weighted correlation network analysisBMC Bioinformatics, 2008
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Overindulgence and metabolic syndrome: is FoxO1 a missing link?JCI Insight, 2008