Bone mesenchymal stem cells (MSCs) can promote liver regeneration and inhibit inflammation and hepatic fibrosis. MSCs also can serve as a vehicle for gene therapy. Smad7 is an essential negative regulatory gene in the TGF-β1/Smad signalling pathway. Activation of TGF-β1/Smad signalling accelerates liver inflammation and fibrosis; we therefore hypothesized that MSCs overexpressing the Smad7 gene might be a new cell therapy approach for treating liver fibrosis via the inhibition of TGF-β1/Smad signalling. MSCs were isolated from 6-week-old Wistar rats and transduced with the Smad7 gene using a lentivirus vector. Liver cirrhosis was induced by subcutaneous injection of carbon tetrachloride (CCl4) for 8 weeks. The rats with established liver cirrhosis were treated with Smad7-MSCs by direct injection of cells into the main lobes of the liver. The expression of Smad7, Smad2/3 and fibrosis biomarkers or extracellular matrix proteins and histopathological change were assessed by quantitative PCR, ELISA and Western blotting and staining. The mRNA and protein level of Smad7 in the recipient liver and serum were increased after treating with Smad-MSCs for 7 and 21 days (P < 0.001). The serum levels of collagen I and III and collagenase I and III were significantly (P < 0.001) reduced after the treatment with Smad7-MSCs. The mRNA levels of TGF-β1, TGFBR1, α-SMA, TIMP-1, laminin and hyaluronic acid were decreased (P < 0.001), while MMP-1 increased (P < 0.001). The liver fibrosis score and liver function were significantly alleviated after the cell therapy. The findings suggest that the MSC therapy with Smad7-MSCs is effective in the treatment of liver fibrosis in the CCl4-induced liver cirrhosis model. Inhibition of TGF-β1 signalling pathway by enhancement of Smad-7 expression could be a feasible cell therapy approach to mitigate liver cirrhosis.

中文翻译：

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基于间充质干细胞的Smad7基因治疗实验性肝硬化。

骨髓间充质干细胞（MSC）可以促进肝脏再生并抑制炎症和肝纤维化。MSC也可以用作基因治疗的载体。Smad7是TGF-β1/ Smad信号通路中必不可少的负调控基因。TGF-β1/ Smad信号的激活会加速肝脏炎症和纤维化。因此，我们假设MSCs过表达可能是通过抑制TGF-β1/ Smad信号转导来治疗肝纤维化的一种新的细胞治疗方法。从6周龄的Wistar大鼠中分离出MSC，并使用慢病毒载体将Smad7基因转导。皮下注射四氯化碳（CCl4）诱导8周，可引起肝硬化。将Smad7-MSCs直接注入肝的主要肺叶中，以Smad7-MSCs处理已建立的肝硬化大鼠。Smad7，Smad2 / 3和纤维化生物标志物或细胞外基质蛋白的表达和组织病理学变化通过定量PCR，ELISA和Western印迹和染色进行评估。用Smad-MSCs处理7天和21天后，受体肝脏和血清中Smad7的mRNA和蛋白水平升高（P <0.001）。用Smad7-MSC治疗后，血清中的胶原蛋白I和III和胶原酶I和III的水平显着降低（P <0.001）。TGF-β1，TGFBR1，α-SMA，TIMP-1，层粘连蛋白和透明质酸的mRNA水平降低（P <0.001），而MMP-1升高（P <0.001）。细胞治疗后，肝纤维化评分和肝功能明显减轻。研究结果表明，在CCl4诱导的肝硬化模型中，采用Smad7-MSC的MSC治疗可有效治疗肝纤维化。通过增强Smad-7表达来抑制TGF-β1信号通路可能是减轻肝硬化的可行细胞疗法。