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.

中文翻译：

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胰岛素可微调控制幼稚多能性和胚外内胚层的自我更新途径

激活素/节点（ActA）和Wnt下游的信号传导可以诱导内胚层分化，还支持多能细胞的自我更新。在这里，我们发现这些明显矛盾的活动已通过胰岛素进行了微调。在不存在胰岛素的情况下，这些细胞因子的组合以上下文相关的方式支持内胚层。当应用于类似于植入前胚胎的幼稚多能细胞时，ActA和Wnt会诱导胚外原始内胚层（PrE），而当应用于已引发的多能表皮干细胞（EpiSC）时，这些细胞因子会诱导成胃阶段的胚胎定形内胚层。在幼稚的胚胎干细胞培养中，我们发现胰岛素补充LIF信号以支持自我更新。但是，将其删除后，LIF，ActA和Wnt信号不仅会诱导PrE分化，同时也支持其扩展。这些PrE培养物的自我更新功能强大，并且在基因表达的基础上，这些细胞类似于早期胚泡期PrE，即一种能同时形成内脏和顶壁内胚层的幼稚内胚层状态。