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Tumor necrosis factor-inducible gene 6 promotes liver regeneration in mice with acute liver injury.
- Source :
-
Stem cell research & therapy [Stem Cell Res Ther] 2015 Mar 11; Vol. 6, pp. 20. Date of Electronic Publication: 2015 Mar 11. - Publication Year :
- 2015
-
Abstract
- Introduction: Tumor necrosis factor-inducible gene 6 protein (TSG-6), one of the cytokines released by human mesenchymal stem/stromal cells (hMSC), has an anti-inflammatory effect and alleviates several pathological conditions; however, the hepatoprotective potential of TSG-6 remains unclear. We investigated whether TSG-6 promoted liver regeneration in acute liver failure.<br />Methods: The immortalized hMSC (B10) constitutively over-expressing TSG-6 or empty plasmid (NC: Negative Control) were established, and either TSG-6 or NC-conditioned medium (CM) was intraperitoneally injected into mice with acute liver damage caused by CCl4. Mice were sacrificed at 3 days post-CM treatment.<br />Results: Higher expression and the immunosuppressive activity of TSG-6 were observed in CM from TSG-6-hMSC. The obvious histomorphological liver injury and increased level of liver enzymes were shown in CCl4-treated mice with or without NC-CM, whereas those observations were markedly ameliorated in TSG-6-CM-treated mice with CCl4. Ki67-positive hepatocytic cells were accumulated in the liver of the CCl4+TSG-6 group. RNA analysis showed the decrease in both of inflammation markers, tnfα, il-1β, cxcl1 and cxcl2, and fibrotic markers, tgf-β1, α-sma and collagen α1, in the CCl4+TSG-6 group, compared to the CCl4 or the CCl4+NC group. Protein analysis confirmed the lower expression of TGF-β1 and α-SMA in the CCl4+TSG-6 than the CCl4 or the CCl4+NC group. Immunostaining for α-SMA also revealed the accumulation of the activated hepatic stellate cells in the livers of mice in the CCl4 and CCl4+NC groups, but not in the livers of mice from the CCl4+TSG-6 group. The cultured LX2 cells, human hepatic stellate cell line, in TSG-6-CM showed the reduced expression of fibrotic markers, tgf-β1, vimentin and collagen α1, whereas the addition of the TSG-6 antibody neutralized the inhibitory effect of TSG-6 on the activation of LX2 cells. In addition, cytoplasmic lipid drops, the marker of inactivated hepatic stellate cell, were detected in TSG-6-CM-cultured LX2 cells, only. The suppressed TSG-6 activity by TSG-6 antibody attenuated the restoration process in livers of TSG-6-CM-treated mice with CCl4.<br />Conclusions: These results demonstrated that TSG-6 contributed to the liver regeneration by suppressing the activation of hepatic stellate cells in CCl4-treated mice, suggesting the therapeutic potential of TSG-6 for acute liver failure.
- Subjects :
- Animals
Carbon Tetrachloride
Cells, Cultured
Chemical and Drug Induced Liver Injury pathology
Culture Media, Conditioned pharmacology
Hepatic Stellate Cells metabolism
Humans
Inflammation immunology
Inflammation pathology
Liver pathology
Liver Regeneration genetics
Male
Mice
Mice, Inbred C57BL
Cell Adhesion Molecules genetics
Inflammation Mediators metabolism
Liver Cirrhosis pathology
Liver Regeneration physiology
Mesenchymal Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1757-6512
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Stem cell research & therapy
- Publication Type :
- Academic Journal
- Accession number :
- 25890163
- Full Text :
- https://doi.org/10.1186/s13287-015-0019-z