Vascularized subcutaneous human liver tissue from engineered hepatocyte/fibroblast sheets in mice
Vascularized subcutaneous human liver tissue from engineered hepatocyte/fibroblast sheets in mice
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DOI：
10.1016/j.biomaterials.2015.06.046
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发表时间：
2015-10-01
期刊：
影响因子：
14
通讯作者：
Eguchi, Susumu
中科院分区：
文献类型：
--
作者：
Sakai, Yusuke;Yamanouchi, Kosho;Eguchi, Susumu
皮下肝组织工程是治疗肝衰竭和遗传性肝病的一种有吸引力的微创方法。然而，由于血管浸润不足（新血管生成），移植失败经常发生，而肝细胞表型和功能的维持需要肝小叶复杂细胞组织的体内发育。在这里，我们描述了一种皮下人肝结构，允许通过移植由粘附在成纤维细胞层上的人原代肝细胞组成的工程细胞片来快速血管化移植物。工程化肝细胞/成纤维细胞片层（EHFSs）在体外显示出血管形成相关生长因子（血管内皮生长因子、转化生长因子β 1和肝细胞生长因子）的上级表达水平。EHFSs发展成血管化的皮下人肝组织，含有糖原储存，合成凝血因子IX，并显示出显着更高的合成率的肝脏特异性蛋白质（白蛋白和α 1抗胰蛋白酶）在体内比组织从肝细胞只片。本研究描述了一种新的血管化人肝器官在小鼠皮肤下发生的方法。这种方法可能对建立肝脏疾病的新型细胞疗法有价值。(C)2015爱思唯尔有限公司版权所有。
Subcutaneous liver tissue engineering is an attractive and minimally invasive approach used to curative treat hepatic failure and inherited liver diseases. However, graft failure occurs frequently due to insufficient infiltration of blood vessels (neoangiogenesis), while the maintenance of hepatocyte phenotype and function requires in vivo development of the complex cellular organization of the hepatic lobule. Here we describe a subcutaneous human liver construction allowing for rapidly vascularized grafts by transplanting engineered cellular sheets consisting of human primary hepatocytes adhered onto a fibroblast layer. The engineered hepatocyte/fibroblast sheets (EHFSs) showed superior expression levels of vascularization-associated growth factors (vascular endothelial growth factor, transforming growth factor beta 1, and hepatocyte growth factor) in vitro. EHFSs developed into vascularized subcutaneous human liver tissues contained glycogen stores, synthesized coagulation factor IX, and showed significantly higher synthesis rates of liver-specific proteins (albumin and alpha 1 anti-trypsin) in vivo than tissues from hepatocyte-only sheets. The present study describes a new approach for vascularized human liver organogenesis under mouse skin. This approach could prove valuable for establishing novel cell therapies for liver diseases. (C) 2015 Elsevier Ltd. All rights reserved.