Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs
Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs
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DOI：
10.1111/j.1365-2362.2011.02637.x
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发表时间：
2012-07-01
影响因子：
5.5
通讯作者：
Sata, Michio
中科院分区：
文献类型：
--
作者：
Nakamura, Toru;Torimura, Takuji;Sata, Michio
欧洲临床投资杂志 2012； 42 (7): 717728 摘要 背景 使用诱导纤维化的二甲基亚硝胺 (DMN) 大鼠模型，我们研究了体外扩增的内皮祖细胞 (EPC) 的移植是否可以重建肝组织并预防肝纤维化。材料和方法 将低密度、贴壁的大鼠骨髓来源的单核细胞在支持用于移植的趋化因子（C-X-C 基序）受体 4 (CXCR4) 阳性 EPC 生长的培养基中培养一周。测试大鼠在 4 周内每周腹腔注射 DMN。在此期间，大鼠每周都接受体内扩增的 EPC 移植。结果 移植的CXCR4阳性扩增的EPC进入汇管束、纤维间隔和肝窦周围，这些位置附近表达基质细胞衍生因子1（SDF-1）（一种吸引CXCR4阳性细胞的配体）。在 EPC 移植大鼠中，我们观察到肝纤维化受到抑制，I 型胶原和纤连蛋白沉积减少，α-平滑肌肌动蛋白阳性细胞减少，转化生长因子 (TGF)-β 表达降低。 EPC移植大鼠中促进肝再生的生长因子（肝细胞生长因子、转化生长因子-a（TGF-a）、表皮生长因子和血管内皮生长因子）的表达显着增加，导致肝细胞增殖。 eNOS 和异凝集素 B4 的免疫组织化学分析表明，EPC 移植动物的肝脏血管密度显着增加，表明窦状血管与内皮重建。肝功能检查显示EPC移植大鼠的转氨酶、总胆红素、总蛋白和白蛋白均维持在正常水平。结论 EPC移植能有效促进肝纤维化损伤组织的重塑；它还可以重建慢性肝损伤的血窦。
Eur J Clin Invest 2012; 42 (7): 717728 Abstract Background Using the dimethylnitrosamine (DMN) rat model of induced fibrosis, we investigated whether transfer of in vitroexpanded endothelial progenitor cells (EPCs) could reconstitute liver tissue and protect against liver fibrosis. Materials and methods Low-density, adherent, rat bone marrow-derived mononuclear cells were cultured for one week in medium supporting the growth of chemokine (C-X-C motif) receptor 4 (CXCR4)-positive EPCs that were used for transplantation. Test rats were treated with weekly intraperitoneal injections of DMN over a period of 4 weeks. During that period, the rats were also transplanted weekly with in vivoexpanded EPCs. Results Transplanted CXCR4-positive expanded EPCs entered around the portal tracts, fibrous septa and hepatic sinusoids, locations at which stromal cellderived factor 1 (SDF-1), a ligand attracting CXCR4-positive cells, was expressed nearby. In EPC-transplanted rats, we observed suppression of liver fibrogenesis, reduced deposition of type I collagen and fibronectin, fewer a-smooth muscle actin-positive cells and lower expression of transforming growth factor (TGF)-beta. The expression of growth factors promoting hepatic regeneration (hepatocyte growth factor, transforming growth factor-a (TGF-a), epidermal growth factor and vascular endothelial growth factor) was significantly increased in EPC-transplanted rats, resulting in hepatocyte proliferation. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Liver function tests of transaminase, total bilirubin, total protein and albumin demonstrated that normal levels were maintained in EPC-transplanted rats. Conclusions EPC transplantation effectively promotes the remodelling of tissues damaged by liver fibrosis; it can also reconstitute sinusoids in chronic liver injury.