Abstract
BackgroundMesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear.MethodsMSCs were isolated from the bone marrow (BM) of 4–6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed.ResultsMSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone.ConclusionsBM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.
Highlights
Alcoholic liver disease (ALD) is a leading cause of chronic liver disease worldwide with high morbidity and mortality [1]
Consistent with these data, we observed that i.p. injection of Mesenchymal stem cells (MSCs) (5 × 106cells/mouse) markedly dampened the systemic and hepatic inflammatory responses as reflected by reduced proinflammatory cytokines (i.e., interleukin (IL)-6, tumor necrosis factor (TNF)-α, cyclo-oxygenase (Cox)-2) (Fig. 2a–h) and elevated anti-inflammatory cytokines (i.e., IL-10, TNF-α-stimulated gene/ protein 6 (TSG-6)) (Fig. 2i–n) in the alcoholic hepatitis (AH)+MSC group as compared to the AH group
Low frequency of MSCs engrafted into the inflamed liver To evaluate the migratory ability of i.p. injected MSCs, we analyzed the hepatic expression of SRY protein by immunofluorescent assay, since SRY was a male sex determinant gene and its expression in female tissue indicated the presence of allogenic cells
Summary
Alcoholic liver disease (ALD) is a leading cause of chronic liver disease worldwide with high morbidity and mortality [1]. AH is a necroinflammatory process that may cause cirrhosis in 40% of cases due to its association with the fastest progression of fibrosis, and patients without AH are at low risk of developing. Oxidative stress, inflammation, and bacterial translocation are known driving factors for ALD, and multiple attempts have been made to improve patient outcomes, there is still no more successful treatment for this illness than alcohol abstinence and corticosteroid exposure to those with severe AH. These treatments are not successful in about 40% of cases [6]. The efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
