The Homeobox Gene Hex Regulates Hepatocyte Differentiation from Embryonic Stem Cell-Derived Endoderm
The Homeobox Gene Hex Regulates Hepatocyte Differentiation from Embryonic Stem Cell-Derived Endoderm
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DOI：
10.1002/hep.23293
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发表时间：
2010-02-01
期刊：
影响因子：
13.5
通讯作者：
Keller, Gordon
中科院分区：
文献类型：
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作者：
Kubo, Atsushi;Kim, Yon Hui;Keller, Gordon
我们研究了在胚胎干细胞(ESC)来源的类胚体(EBS)中，造血表达的同源异型盒(Hex)在肝细胞分化和发育中的作用。对来自Hex(-/-)EBS的肝内胚层的分析显示，白蛋白(Alb)和甲胎蛋白(AFP)的表达水平显著降低。相反，野生型ESCs在EBS中的阶段特异性强制表达导致Alb和AFP表达上调，Alb和转铁蛋白分泌增加。这些诱导作用仅限于c-kit(+)内胚层丰富的EB来源的群体，提示在该模型中，Hex在肝内胚层水平上起作用。微阵列分析显示，Hex调控广泛的肝细胞相关基因的表达，包括纤维蛋白原、载脂蛋白和细胞色素。骨形态发生蛋白4加入内胚层诱导的EBS中，与Hex协同诱导Alb、AFP、氨基甲酰磷酸合成酶、转录因子1和CCAAT/增强子结合蛋白α的表达。这些发现表明，在这个体外模型中，Hex在从内胚层诱导肝脏发育过程中起着关键作用，并表明这一策略可能为从ESCs生成功能肝细胞提供重要的见解。(《肝病》2010；51：633-641。)
We investigated the role of the hematopoietically expressed homeobox (Hex) in the differentiation and development of hepatocytes within embryonic stem cell (ESC)-derived embryoid bodies (EBs). Analyses of hepatic endoderm derived from Hex(-/-) EBs revealed a dramatic reduction in the levels of albumin (Alb) and alpha-fetoprotein (Afp) expression. In contrast, stage-specific forced expression of Hex in EBs from wild-type ESCs led to the up-regulation of Alb and Afp expression and secretion of Alb and transferrin. These inductive effects were restricted to c-kit(+) endoderm-enriched EB-derived populations, suggesting that Hex functions at the level of hepatic specification of endoderm in this model. Microarray analysis revealed that Hex regulated the expression of a broad spectrum of hepatocyte-related genes, including fibrinogens, apolipoproteins, and cytochromes. When added to the endoderm-induced EBs, bone morphogenetic protein 4 acted synergistically with Hex in the induction of expression of Alb, Afp, carbamoyl phosphate synthetase, transcription factor 1, and CCAAT/enhancer binding protein alpha. These findings indicate that Hex plays a pivotal role during induction of liver development from endoderm in this in vitro model and suggest that this strategy may provide important insight into the generation of functional hepatocytes from ESCs. (HEPATOLOGY 2010;51:633-641.)