Activin B mediated induction of Pdx1 in human embryonic stem cell derived embryoid bodies.
Human embryonic stem cells (hESCs) have the potential to provide alternative sources for pancreatic islet grafts. In the present study we have investigated the influence of Activin A and Activin B on the expression of the pancreas marker gene Pdx1 in hESCs differentiated as embryoid bodies (EBs). We report here that Activin B in a dose depend manner markedly up-regulates Pdx1 expression as compared to Activin A and untreated cultures. Pdx1(+) cells co-express FOXA2 but lacks, however, co-expression with nkx6.1, a marker combination that in the present study is shown precisely to identify embryonic and fetal pancreas anlage in humans. Pdx1(+) cells are found in cell clusters also expressing Serpina1 and FABP1, suggesting activation of intestinal/liver developmental programs. Moreover, Activin B up-regulates Sonic Hedgehog (Shh) and its target Gli1, which during normal development is suppressed in the pancreatic anlage. In conclusion, Activin B is a potent inducer of Pdx1 as well as Shh in differentiating hESCs. The data suggest that additional suppression of Shh signaling may be required to allow for proper specification of pancreatic cell lineages in hESCs.
Frandsen
Ulrik
U
KMEB Laboratory, Medical Biotechnology Center, Winslevparken 25.1, DK-5000 Odense C, Denmark. ufrandsen@health.sdh.dk
Porneki
Ann Dorte
AD
Floridon
Charlotte
C
Abdallah
Basem M
BM
Kassem
Moustapha
M
D028341:Activins / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology*; D004707:Endoderm / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D051379:Mice; D010179:Pancreas / Q000196:embryology*; D013724:Teratoma / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis*
D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D015534:Trans-Activators; C044147:activin B; C084010:pancreatic and duodenal homeobox 1 protein; D028341:Activins