Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes
Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes
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DOI：
10.1038/nbt1257
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发表时间：
2006-11-01
影响因子：
46.9
通讯作者：
Fox, Ira J.
中科院分区：
文献类型：
--
作者：
Soto-Gutierrez, Alejandro;Kobayashi, Naoya;Fox, Ira J.
严重的急性肝功能衰竭，即使是短暂的，必须通过移植和终身免疫抑制治疗。治疗可以通过生物人工肝（BAL）支持来改善，但这种方法受到人类肝细胞短缺的阻碍。为了产生用于BAL支持的细胞的替代来源，我们通过与人肝非实质细胞系和成纤维细胞生长因子-2、人激活素A和肝细胞生长因子的组合共培养将小鼠胚胎干（ES）细胞分化成肝细胞。使用基于白蛋白启动子的细胞分选分离功能性肝细胞。ES细胞来源的肝细胞表达肝特异性基因，分泌白蛋白，代谢氨、利多卡因和安定.用皮下植入的接种有ES细胞衍生的肝细胞或原代肝细胞的BAL治疗90%肝切除的小鼠，改善了肝功能并延长了存活期，而用接种有对照细胞的BAL治疗则没有。在BAL中发挥功能后，ES细胞衍生的肝细胞发展出与原代肝细胞几乎相同的特征。
Severe acute liver failure, even when transient, must be treated by transplantation and lifelong immune suppression. Treatment could be improved by bioartificial liver ( BAL) support, but this approach is hindered by a shortage of human hepatocytes. To generate an alternative source of cells for BAL support, we differentiated mouse embryonic stem (ES) cells into hepatocytes by coculture with a combination of human liver nonparenchymal cell lines and fibroblast growth factor- 2, human activin A and hepatocyte growth factor. Functional hepatocytes were isolated using albumin promoter - based cell sorting. ES cell - derived hepatocytes expressed liver- specific genes, secreted albumin and metabolized ammonia, lidocaine and diazepam. Treatment of 90% hepatectomized mice with a subcutaneously implanted BAL seeded with ES cell - derived hepatocytes or primary hepatocytes improved liver function and prolonged survival, whereas treatment with a BAL seeded with control cells did not. After functioning in the BAL, ES cell - derived hepatocytes developed characteristics nearly identical to those of primary hepatocytes.