| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Yuzo Kyoto University, Gastroenterological Surgery, Lecturer, 医学研究科, 講師 (70281730)
IKAI Iwao Kyoto University, Gastroenterological Surgery, Lecturer, 医学研究科, 講師 (60263084)
YAMAOKA Yoshio Kyoto University, Gastroenterological Surgery, Professor, 医学研究科, 教授 (90089102)
MORIMOTO Taisuke Kyoto University, Gastroenterological Surgery, former Lecturer, 医学研究科, 前講師 (60135910)
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| Research Abstract |
Remodeling of hepatic extracellular matrix has been supposed to participate in liver regeneration. We investigated whether increased activity of collagenase in the liver could induce hepatocyte proliferation in vivo. Gene transfer of collagenase with a recombinant adenovirus Ad5MMP-1 induced significant increase in BrdU labeling index and mitotic index in hepatocytes, leading to an increased dried liver weight, while a control adenovirus, Ad5LacZ, had a minimal effect. Hepatocyte proliferation started around 48hr after the infection with Ad5MMP-1 and almost ended at 2weeks. Transient liver injury indicated by increased AST, ALT, and LDH with peaks around 1 week was also detected after Ad5MMP-1 infection, accompanied by apoptosis in hepatocytes. As important phenomena during collagenase-induced hepatocyte proliferation, phosphorylation of glycogen synthase kinase (GSK)-3β at serine residue, accumulation of β-catenin in cytoplasm of hepatocytes, and transient decrease in E-cadherin expre
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ssion were observed. Thus, we report that modification of hepatic extracellular matrix by collagenase induces transient hepatocyte proliferation in vivo, suggesting that the condition of hepatic extracellular matrix per se plays a pivotal role in regulating hepatocyte proliferation.
In another experiment, we hypothesized that failure to resolve the hepatic fibrous scar results from the imbalance between too little interstitial collagenases (MMP-1 or MMP-13) and too much ECM and TIMPs. We tested this hypothesis by transiently changing the balance by using gene therapy to deliver MMP-1 in a rat model of persistent liver fibrosis. In Ad5MMP-1 infected, but not in Ad5LacZ infected, rats the fibrosis was dramatically attenuated at 2 weeks after the infection. Interestingly, the number of activated hepatic stellate cells was also decreased in Ad5MMP-1 infected rats. Moreover, disorganization of hepatic trabecule, heterogeneity in size of hepatocytes, and increased dried liver weight were observed only in Ad5MMP-1 treated rats, suggesting that MMP-1 stimulated hepatocyte proliferation, which was confirmed by BrdU staining. Our findings demonstrate that transient MMP-1 overexpression in the liver effectively attenuates established fibrosis and induces hepatocyte proliferation. Less
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