Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model |
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Authors: | Nakamura Toru Torimura Takuji Sakamoto Masaharu Hashimoto Osamu Taniguchi Eitaro Inoue Kinya Sakata Ryuichiro Kumashiro Ryukichi Murohara Toyoaki Ueno Takato Sata Michio |
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Affiliation: | Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan. ntoru@med.kurume-u.ac.jp |
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Abstract: | BACKGROUND & AIMS: We investigated whether endothelial progenitor cell (EPC) transplantation could reduce established liver fibrosis and promote hepatic regeneration by isolating rat EPCs from bone marrow cells. METHODS: Recipient rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 6 weeks before initial administration of EPCs. CCl(4) was then readministered twice weekly for 4 more weeks, and EPC transplantation was carried out for these same 4 weeks. RESULTS: At 7 days in culture, the cells expressed Thy-1, CD31, CD133, Flt-1, Flk-1, and Tie-2, suggesting an immature endothelial lineage. Immunohistochemical analyses showed fluorescent-labeled, transplantation EPCs were incorporated into the portal tracts and fibrous septa. Single and multiple EPC transplantation rats had reduced liver fibrosis, with decreased alpha2-(I)-procollagen, fibronectin, transforming growth factor-beta, and alpha-smooth muscle actin-positive cells. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area, in accordance with EPC location. Real-time polymerase chain reaction analysis of multiple EPC-transplantation livers showed significantly increased messenger RNA levels of matrix metalloproteinase (MMP)-2, -9 and -13, whereas tissue inhibitor of metalloproteinase-1 expression was significantly reduced. Expression of hepatocyte growth factor, transforming growth factor-alpha, epidermal growth factor, and vascular endothelial growth factor was increased in multiple EPC-transplantation livers, while hepatocyte proliferation increased. Transaminase, total bilirubin, total protein, and albumin levels were maintained in EPC-transplantation rats, significantly improving survival rates. CONCLUSIONS: We conclude that single or repeated EPC transplantation halts established liver fibrosis in rats by suppressing activated hepatic stellate cells, increasing matrix metalloproteinase activity, and regulating hepatocyte proliferation. |
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Keywords: | α-SMA, α-smooth muscle actin BM, bone marrow CCl4, carbon tetrachloride ECM, extracellular matrix EGF, epithelial growth factor EPC, endothelium progenitor cell Flk-1, fetal liver kinase-1 Flt-1, fms-like tyrosine kinase-1 HGF, hepatocyte growth factor HSC, hepatic stellate cell MMP, matrix metalloproteinase RAECs, rat aortic endothelial cells TAA, thioacetamide TGF, transforming growth factor Tie-2, tyrosine kinase with Ig and EGF homology domains-2 TIMP, tissue inhibitor of metalloproteinase VEGF, vascular endothelial growth factor |
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