HGF/c-Met signaling mediated mesenchymal stem cell-induced liver recovery in intestinal ischemia reperfusion model.
HGF/c-Met signaling mediated mesenchymal stem cell-induced liver recovery in intestinal ischemia reperfusion model.
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DOI：
10.7150/ijms.8228
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发表时间：
2014
影响因子：
3.6
通讯作者：
Huang P
中科院分区：
文献类型：
--
作者：
Liu J;Pan G;Liang T;Huang P
目的：肠缺血再灌注（IIR）引起的肝损伤通常预示着多器官功能障碍和死亡。最近的研究表明，间充质干细胞（MSCs）具有保护器官损伤的潜力。由于相关证据不足，机制还不清楚，我们研究了肝细胞生长因子c-Met信号转导（HGF/c-Met）对大鼠模型中骨髓间充质干细胞募集和随后对IIR引发的肝损伤的保护作用。方法：采用上级肠系膜上动脉阻断75 min，再灌注4 h的方法建立大鼠IIR模型。将纯MSC和经HGF或SU 11274（c-Met抑制剂）预处理的MSC注射到大鼠模型中。通过检测肝脏生化和病理学变化，评价MSCs和药物治疗的疗效。同时，体外实验观察HGF和SU 11274对MSCs中c-Met和磷酸化Met表达以及MSCs迁移的影响。结果：IIR肝损伤主要表现为血清ALT、AST、HGF水平升高及肝组织病理改变。高表达c-Met的MSCs可减轻血清转氨酶升高和肝脏病理改变，而SU 11274可减弱这种作用。HGF可上调MSCs中c-Met和磷酸化Met的表达，增强其保肝作用。Transwell实验表明HGF促进MSCs迁移，而SU 11274可阻断HGF促进MSCs迁移。结论：HGF/c-Met信号通路在MSCs向肠缺血再灌注损伤肝脏归巢，进而介导MSCs诱导的肝脏修复过程中发挥重要作用。
Purpose: Liver injury triggered by intestinal ischemia-reperfusion (IIR) usually presage multiorgan dysfunction and death in patients. Recent studies suggest mesenchymal stem cells (MSCs) possess a protective potential against organ damage. Since relative evidence is insufficient and the mechanism is not well understood, we investigated the effect of hepatocyte growth factor c-Met signaling (HGF/c-Met) on recruitment of MSCs and subsequent protection against liver injury triggered by IIR in a rat model. Methods: IIR models were built as rats were subjected to 75 min of superior mesenteric artery occlusion and subsequent 4 h reperfusion. Either of pure MSCs and MSCs pretreated with HGF or SU11274 (c-Met inhibitor) were injected into rat models. Biochemical and pathologic alterations of liver in IIR model were measured to evaluate the therapeutic effect of MSCs and drug treatment. Concurrently, the effect of HGF and SU11274 on c-Met and phosphorylated Met expression in MSCs and MSCs migration were assessed in in vitro experiment. Results: IIR-induced liver injury was manifested by significant increase in serum ALT, AST and HGF levels as well as pathological change. MSCs with highly c-Met expression ameliorated the increase of serum transaminase levels and hepatic histopathological change, while SU11274 weaken these effects. HGF upregulated c-Met and phosphorylated Met expression in MSCs and enhanced its liver protection effect. Transwell assays demonstrated HGF promoted MSCs migration, which was blocked by SU11274. Conclusions: HGF/c-Met signaling pathway plays an essential role in the homing of MSCs towards injured liver triggered by intestinal ischemia-reperfusion, and then mediates MSC-induced liver repair.
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作者：
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