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.
Highlights
Obesity is a prevalent health problem worldwide, which has been attributed mainly to Western-style diets in combination with reduced physical activity
We and others have shown that the transplantation of mesenchymal stromal cells into mice suffering from non-alcoholic steatohepatitis (NASH) attenuated the lipid load, reduced inflammation, and resolved fibrosis [18,34,59,60]
We aimed by omics approaches in combination with network analyses to identify pathways and key players in NASH, which were affected by Mesenchymal stromal cell (MSC)
Summary
Obesity is a prevalent health problem worldwide, which has been attributed mainly to Western-style diets in combination with reduced physical activity. It is often associated with metabolic co-morbidities, such as diabetes type 2 and non-alcoholic fatty liver diseases (NAFLD), the latter of which has a global prevalence of 24% and is currently the leading cause of chronic liver disease in Europe and in the USA [1]. Impairment of lipid metabolism may cause an imbalance of utilization and storage, eventually contributing to hepatocyte lipid overload. Lipotoxicity induces endoplasmic reticulum (ER) stress, leading to calcium release from the ER, raising cytosolic calcium levels, which in turn interferes with protective autophagy and inhibits the breakdown of lipids, aggravating cellular lipid overload [5]
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