Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Stem Cells Dev. 2010 Jun;19(6):903-14. doi: 10.1089/scd.2009.0254.
Ischemia-reperfusion and chronic injuries associated with small-for-size liver transplantation (SFSLT) impair the regeneration of liver graft and induce liver fibrosis. Mesenchymal stem cells (MSCs) can prevent the development of liver fibrosis, and hepatocyte growth factor (HGF) can also attenuate liver cirrhosis. Our previous studies have demonstrated that higher occurrence of liver fibrosis existed in rats post-SFSLT, and that implantation of HGF/MSCs, the human HGF (hHGF)-expressing MSCs, can improve liver regeneration, reduce mortality of rats, as well as have the potent antifibrotic effect in this SFSLT model. In the present study, we implanted HGF/MSCs into liver grafts via the portal vein and investigated their role in antifibrosis effect, using a 30% SFSLT rat model. Fibrosis indexes, including laminin (LN), hyaluronic acid (HA) levels in serum and hydroxyproline (Hyp) content in the liver grafts, the expression of transforming growth factor-beta1 (TGF-beta(1)), rat HGF (rHGF), alpha-smooth muscle actin (alpha-SMA) in hepatic stellate cells (HSCs), alanine aminotransferase (ALT), total bilirubin (BIL), and albumin (ALB) levels in serum, in rats in different treatment groups were assessed at different time points. We found that HGF/MSCs significantly inhibited the formation of liver fibrosis in rats undergoing SFSLT, while MSCs and HGF had synergistic effects in the process. The antifibrosis effect of HGF/MSCs may have contributed in modulating the activation and apoptosis of HSCs, elevating the rHGF expression level, and decreasing the TGF-beta(1) secretion of activated HSCs. These studies suggest that HGF/MSCs may be a novel therapeutic option for the treatment of liver fibrosis after SFSLT.
缺血再灌注和慢性损伤与小体积肝移植（SFSLT）相关，可损害肝移植物的再生并诱导肝纤维化。间充质干细胞（MSCs）可预防肝纤维化的发展，肝细胞生长因子（HGF）也可减轻肝硬化。我们之前的研究表明，SFSLT 后大鼠肝纤维化的发生率较高，HGF/MSC （表达人 HGF 的 MSC）的植入可改善肝再生，降低大鼠死亡率，并在该 SFSLT 模型中具有强大的抗纤维化作用。在本研究中，我们通过门静脉将 HGF/MSC 植入肝移植物中，并研究了它们在抗纤维化作用中的作用，使用 30%SFSLT 大鼠模型。在不同治疗组的大鼠中，在不同时间点评估了纤维化指标，包括血清层粘连蛋白（LN）、透明质酸（HA）水平和肝移植物羟脯氨酸（Hyp）含量、转化生长因子-β1（TGF-β1）、大鼠 HGF（rHGF）、肝星状细胞（HSCs）中的α-平滑肌肌动蛋白（α-SMA）、丙氨酸氨基转移酶（ALT）、总胆红素（BIL）和血清白蛋白（ALB）水平。我们发现 HGF/MSC 可显著抑制 SFSLT 大鼠肝纤维化的形成，而 MSC 和 HGF 在该过程中具有协同作用。HGF/MSC 的抗纤维化作用可能通过调节 HSCs 的激活和凋亡、提高 rHGF 表达水平和减少活化 HSCs 的 TGF-β1 分泌来发挥作用。这些研究表明，HGF/MSC 可能是治疗 SFSLT 后肝纤维化的一种新的治疗选择。
