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The homeobox gene Hex regulates hepatocyte differentiation from embryonic stem cell–derived endoderm
Author(s) -
Kubo Atsushi,
Kim Yon Hui,
Irion Stefan,
Kasuda Shogo,
Takeuchi Mitsuaki,
Ohashi Kazuo,
Iwano Masayuki,
Dohi Yoshiko,
Saito Yoshihiko,
Snodgrass Ralph,
Keller Gordon
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23293
Subject(s) - endoderm , embryoid body , biology , homeobox , microbiology and biotechnology , embryonic stem cell , cell fate determination , hepatocyte , transcription factor , gene , genetics , induced pluripotent stem cell , in vitro
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 α. 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. (H EPATOLOGY 2010.)