The homeobox gene Hex regulates hepatocyte differentiation from embryonic stem cell-derived endoderm.
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.
Kubo
Atsushi
A
First Department of Internal Medicine, Nara Medical University, Nara, Japan. akubo@naramed-u.ac.jp
Kim
Yon Hui
YH
Irion
Stefan
S
Kasuda
Shogo
S
Takeuchi
Mitsuaki
M
Ohashi
Kazuo
K
Iwano
Masayuki
M
Dohi
Yoshiko
Y
Saito
Yoshihiko
Y
Snodgrass
Ralph
R
Keller
Gordon
G
D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells; D004707:Endoderm / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology*; D018398:Homeodomain Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors