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Development. 2011 Mar;138(5):861-71. doi: 10.1242/dev.055236. Epub 2011 Jan 26.

Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells.

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  • 1McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.

Erratum in

  • Development. 2011 Mar;138(5).doi: 10.1242/dev.065904.
  • Development. 2011 Apr;138(7):1445.

Abstract

The generation of insulin-producing β-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFβ family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+ cells.

PMID:
21270052
[PubMed - indexed for MEDLINE]
PMCID:
PMC3035090
Free PMC Article
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