Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm – University of Copenhagen

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02 October 2017

Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm

Anderson, Kathryn G.V., William B. Hamilton, Fabian V. Roske, Ajuna Azad, Teresa E. Knudsen, Maurice A. Canham, Lesley M. Forrester&  Joshua M. Brickman (2017). Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm. Nature Cell Biology, 19(10), 1164–1177, doi: 10.1038/ncb3617.

Abstract

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.