Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

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.

A Multi-Omics Analysis of Mucosal-Associated-Invariant T Cells Reveals Key Drivers of Distinct Modes of Activation

“…Next, we aimed to identify relevant molecules defining the distinct expression signatures in the two ways of activation. Hence, we performed a Weighted Gene Correlation Network Analysis (WGCNA) ( 38 ), offering a differential-expression-independent analysis suitable to identify novel key drivers of biological treatments ( 32 , 38 , 59 , 66 , 67 ). Considering all the 36,484 quantified transcripts from the two treatment groups and the control group, we obtained 25 modules, containing genes with similar expression pattern, named by colors ( Figure 4A , Supplementary Figure 3A ).…”

Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages

“…For example, changes in the central carbon metabolism are reported very often since the central carbon metabolism responds to stimuli sensitively. Unfortunately, these changes are rather unspecific since they can be related to various processes such as aging [ 163 ], cancer [ 164 ], diseases like non-alcoholic steatohepatitis (NASH) [ 165 ], and macrophage activation [ 166 ] for instance. Abundance-based information on metabolites involved in the central carbon metabolism, as obtained by metabolomics, do not necessarily give information whether the pathway was upregulated or downregulated.…”

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

“…Lately, cell-based therapy has emerged as a feasible alternative for the treatment of different stages of NAFLD. In particular, experimental evidence supports the use of bone marrow- [ 187 ], umbilical cord- [ 188 ], and compact bone-derived mesenchymal stromal cells [ 189 ] as well as hepatocytes derived by differentiating induced pluripotent stem cells [ 190 ]. The crosstalk between hepatic stem cells and their possible therapeutic application for NAFLD are discussed in detail in a recent review by Overi et al [ 191 ].…”