Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells
Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells
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DOI：
10.1016/j.jhep.2011.01.036
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发表时间：
2011-10-01
影响因子：
25.7
通讯作者：
Prieto, Jesus
中科院分区：
文献类型：
--
作者：
Fernandez-Ruiz, Veronica;Kawa, Milosz;Prieto, Jesus
背景与目的：细胞疗法已被用于减轻肝损伤。在这里，我们评估了骨髓来源的单个核细胞(MNC)或内皮祖细胞(EPC)的基因工程是否可以增强它们的肝脏保护性能。方法：ConA诱导性肝炎或致死性暴发型肝炎的小鼠接受脾内注射生理盐水或2×10(6)未经修饰的MNC或EPC或体外转导表达荧光素酶的腺病毒(MNCLUC和EPCLUC)或编码肝保护细胞因子心肌营养素-1(MNCCT-1和EPCCT-1)的相同细胞。结果：荧光素酶免疫组织化学显示，注射入脾后，工程化细胞能有效地向受损肝脏迁移。在患有ConA肝炎的小鼠中，EPCCT-1，但不是其他形式的细胞治疗，显著降低了血清转氨酶，并诱导了比其他治疗更强烈的组织学改善。其显著疗效与IGF-I、EGF等细胞保护分子表达上调、促炎细胞因子、IL-1b、TNF-α表达降低、颗粒酶B水平降低有关。在AdCD40L诱导的致死性重型肝炎中，EPCCT-1在抑制促炎介质的表达和肝脏损伤方面也优于其他细胞疗法，其他治疗组的存活率为35.7%，死亡率为100%。结论：高表达CT-1的EPC基因工程增强了EPC的保肝作用，是一种值得考虑的急性肝功能衰竭的治疗方法。(C)2011年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties.Methods: Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 x 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival.Results: Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNF alpha, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups.Conclusions: Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.