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Embryonic Stem Cells |
1 Cell Differentiation Unit, Diabetes Research Center - Vrije Universiteit Brussel (VUB), Brussels, Belgium
2 Medical Biochemistry Unit, Diabetes Research Center - Vrije Universiteit Brussel (VUB), Brussels, Belgium
* To whom correspondence should be addressed. E-mail: lucbo{at}vub.ac.be.
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Abstract |
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Success of cell replacement therapy for diabetes will largely depend on the establishment of alternative sources of pancreatic islet grafts. Embryonic stem (ES) cell differentiation towards pancreatic insulin-producing cells offers such perspectives, but there are still many challenges to overcome. Our previous studies suggested that the limited amount of insulin+ cells derived from ES cells is related to the activation of pancreas inhibitory signals. To confirm this hypothesis, we report here that exposure of mouse embryonic pancreas explants to soluble factors from embryoid bodies (EBs) inhibits growth, morphogenesis, endocrine and exocrine differentiation as evaluated by explant size, mRNA and protein expression. Shh, an established pancreas repressor both at early and late developmental stages was produced and secreted by EBs, and participated in the inhibitory effect by inducing its target Gli1 in the explants. Inhibition of Hedgehog pathway rescued the differentiation of Insulin+ cells in the explants. In contrast to pancreatic cells, hepatic progenitors exposed to EBs conditioned medium showed improved differentiation of albumin-positive cells. In a model system of ES cell differentiation in vitro, we found that definitive endoderm induction by serum removal or Activin A treatment further increased Hedgehog production and activity in EBs. Concomitantly, down-regulation of the pancreas marker Pdx1 was recorded in Activin-treated EBs, a phenomenon that was prevented by antagonizing Hedgehog signaling with Hedgehog interacting protein. These data strongly suggest that Hedgehog production in EBs limits pancreatic fate acquisition and forms a major obstacle in the specification of pancreatic cells from ES-derived definitive endoderm.
Key Words. Activin, Beta cells, Definitive endoderm, Embryonic stem cells, Hedgehog, Pancreas development
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