HGF/c-Met signaling mediated mesenchymal stem cell-induced liver recovery in intestinal ischemia reperfusion model.
OBJECTIVE
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.
1. Department of Gastrointestinal Surgery;
Jianpei
J
Liu
2. Liver Transplantation Center;
Guozheng
G
Pan
3. Department of Articular Surgery;
Tangzhao
T
Liang
4. Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Pinjie
P
Huang
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008099:Liver / Q000293:injuries / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology / Q000628:therapy*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C081092:HGF activator; D012697:Serine Endopeptidases
Mesenchymal stem cell; hepatocyte growth factor; intestine; ischemia reperfusion; liver injury