Journal
NATURE CELL BIOLOGY
Volume 19, Issue 10, Pages 1164-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3617
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Funding
- Novo Nordisk Foundation Center for Stem Cell Biology
- Danish National Research Foundation [DNRF 116]
- MRC UK
- University of Copenhagen
- Novo Nordisk Foundation Section for Basic Stem Cell Biology [Brickman group NNF] Funding Source: researchfish
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Signalling downstream of Activin/Nodal (ActA) and Wnt can induce endoderm differentiation and also support self-renewal in pluripotent cells. Here we find that these apparently contradictory activities are fine-tuned by insulin. In the absence of insulin, the combination of these cytokines supports endoderm in a context-dependent manner. When applied to naive pluripotent cells that resemble peri-implantation embryos, ActA and Wnt induce extra-embryonic primitive endoderm (PrE), whereas when applied to primed pluripotent epiblast stem cells (EpiSC), these cytokines induce gastrulation-stage embryonic definitive endoderm. In naive embryonic stem cell culture, we find that insulin complements LIF signalling to support self-renewal; however, when it is removed, LIF, ActA and Wnt signalling not only induce PrE differentiation, but also support its expansion. Self-renewal of these PrE cultures is robust and, on the basis of gene expression, these cells resemble early blastocyst-stage PrE, a naive endoderm state able to make both visceral and parietal endoderm.
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