Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling.
Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling has been shown to play important roles in coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development in vivo. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our in vitro model, demonstrating the importance of a physiologic approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepatocellular function in vitro and in vivo. In addition, we demonstrate that Wnt3a facilitates clonal plating of hESCs exhibiting functional hepatic differentiation. These studies represent an important step toward the use of hESC-derived hepatocytes in high-throughput metabolic analysis of human liver function.
Hay
David C
DC
Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom. davehay@talktalk.net
Fletcher
Judy
J
Payne
Catherine
C
Terrace
John D
JD
Gallagher
Ronald C J
RC
Snoeys
Jan
J
Black
James R
JR
Wojtacha
Davina
D
Samuel
Kay
K
Hannoun
Zara
Z
Pryde
Anne
A
Filippi
Celine
C
Currie
Ian S
IS
Forbes
Stuart J
SJ
Ross
James A
JA
Newsome
Philip N
PN
Iredale
John P
JP
D028341:Activins / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000637:transplantation; D006801:Humans; D008099:Liver / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C422405:activin A; D028341:Activins