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Abstract

Background and Objective: Regenerative medicine through stem cells holds a great promise and potential therapeutics to regenerate the damaged tissue. Exosomes through their complex cargo of proteins and genetic materials can potentiate treatment of damaged tissues and circumvents some of the concerns and limitations in using viable replicating stem cell. The therapeutic effect of bone marrow mesenchymal stem cells (BM-MSC)-derived exosomes on diethylnitrosamine-induced liver injury was explored in the present study. Materials and Methods: The MSCs were isolated from rats&#146; bone marrow and characterized by flow cytometry. Exosomes were isolated from MSCs through gradient ultracentrifugation and identified by transmission electron microscopy. Liver was injured with a single intraperitoneal injection of 100 mg kg&#150;1 diethylnitrosamine in 1 mL PBS. BM-MSCs-exosomes were intravenously injected in liver-injured rats. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and albumin were measured. Liver homogenate levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and malondialdehyde (MDA) were measured. Cellular changes have been investigated through histopathological examination and relative quantitative polymerase chain reaction (qPCR) of Bax, Bcl2, Tgfβ1, Tnfa, Cox2 and NFkB transcripts. Data were analyzed by one-way ANOVA followed by Tukey's Honestly Significant Difference test. Significance was considered at p<0.05. Results: MSCs-exosomes significantly reduced serum levels of liver enzymes ALT, AST and ALP, as compared to liver-injured rats. Exosomes also significantly improved the antioxidant enzymatic activities of SOD, CAT, GPx and decreased MDA in liver tissues. In addition to restoration of the deteriorated hepatic histology, exosomes also inhibited expression of the apoptotic gene, Bax and the tissue transforming gene, Tgfβ, whereas they induced the expression of the anti-apoptotic gene, Bcl2 and liver regeneration-related genes, TNFa, NFkB, Cox2. Conclusion: These results suggest ameliorative effect for exosomes on liver injury through induction of liver cells regeneration and inhibition of oxidative stress, apoptosis and epithelial-to mesenchymal transition (EMT) marker, which may be helpful to understand the mechanism of liver diseases and highlight new therapeutic strategies for these diseases.