BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm
BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm
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DOI：
10.1038/nbt1258
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发表时间：
2006-11-01
影响因子：
46.9
通讯作者：
Keller, Gordon
中科院分区：
文献类型：
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作者：
Gouon-Evans, Valerie;Boussemart, Lise;Keller, Gordon
在无血清条件下，在激活素A存在的情况下进行分化时，小鼠胚胎干细胞能有效地产生一种内胚层祖细胞群，其特征是同时表达短尾畸形相关转录因子（Brachyury）、叉头框蛋白A2（Foxa2）和c - Kit，或者c - Kit和Cxcr4。用骨形态发生蛋白 - 4结合碱性成纤维细胞生长因子和激活素A对这些祖细胞进行定向诱导，会产生高度富集（45 - 70%）表达甲胎蛋白和白蛋白的细胞的肝脏细胞群。这些细胞还表达甲胎蛋白（Afp）、白蛋白1（Alb1）、酪氨酸转氨酶（Tat）、氨甲酰磷酸合成酶1（Cps1）、胆固醇7α - 羟化酶（Cyp7a1）和细胞色素P450 3A11（Cyp3a11）的转录本；它们分泌白蛋白，储存糖原，显示出成熟肝细胞的超微结构特征，并且能够在体内整合到受损肝脏中并增殖，成熟为表达二肽基肽酶IV或延胡索酰乙酰乙酸水解酶的肝细胞。总之，这些发现确立了胚胎干细胞分化培养中的一种发育途径，该途径可高效产生具有未成熟肝细胞表型的细胞。
When differentiated in the presence of activin A in serum-free conditions, mouse embryonic stem cells efficiently generate an endoderm progenitor population defined by the coexpression of either Brachyury, Foxa2 and c- Kit, or c- Kit and Cxcr4. Specification of these progenitors with bone morphogenetic protein- 4 in combination with basic fibroblast growth factor and activin A results in the development of hepatic populations highly enriched ( 45 - 70%) for cells that express the alpha- fetoprotein and albumin proteins. These cells also express transcripts of Afp, Alb1, Tat, Cps1, Cyp7a1 and Cyp3a11; they secrete albumin, store glycogen, show ultrastructural characteristics of mature hepatocytes, and are able to integrate into and proliferate in injured livers in vivo and mature into hepatocytes expressing dipeptidyl peptidase IV or fumarylacetoacetate hydrolase. Together, these findings establish a developmental pathway in embryonic stem cell differentiation cultures that leads to efficient generation of cells with an immature hepatocytic phenotype.