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Tumor necrosis factor-inducible gene 6 promotes liver regeneration in mice with acute liver injury

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 inv...

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Detalles Bibliográficos
Autores principales: Wang, Sihyung, Lee, Ji-Seon, Hyun, Jeongeun, Kim, Jieun, Kim, Seung U, Cha, Hyuk-Jin, Jung, Youngmi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396561/
https://www.ncbi.nlm.nih.gov/pubmed/25890163
http://dx.doi.org/10.1186/s13287-015-0019-z
Descripción
Sumario: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. 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 CCl(4). Mice were sacrificed at 3 days post-CM treatment. 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 CCl(4)-treated mice with or without NC-CM, whereas those observations were markedly ameliorated in TSG-6-CM-treated mice with CCl(4). Ki67-positive hepatocytic cells were accumulated in the liver of the CCl(4) + 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 CCl(4) + TSG-6 group, compared to the CCl(4) or the CCl(4) + NC group. Protein analysis confirmed the lower expression of TGF-β1 and α-SMA in the CCl(4) + TSG-6 than the CCl(4) or the CCl(4) + NC group. Immunostaining for α-SMA also revealed the accumulation of the activated hepatic stellate cells in the livers of mice in the CCl(4) and CCl(4) + NC groups, but not in the livers of mice from the CCl(4) + 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 CCl(4). CONCLUSIONS: These results demonstrated that TSG-6 contributed to the liver regeneration by suppressing the activation of hepatic stellate cells in CCl(4)-treated mice, suggesting the therapeutic potential of TSG-6 for acute liver failure. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-015-0019-z) contains supplementary material, which is available to authorized users.