Conserved and Divergent Roles of FGF Signaling in Mouse Epiblast Stem Cells and Human Embryonic Stem Cells

SummaryMouse epiblast stem cells (EpiSCs) are cultured with FGF2 and Activin A, like human embryonic stem cells (hESCs), but the action of the associated pathways in EpiSCs has not been well characterized. Here, we show that activation of the Activin pathway promotes self-renewal of EpiSCs via direct activation of Nanog, whereas inhibition of this pathway induces neuroectodermal differentiation, like in hESCs. In contrast, the different roles of FGF signaling appear to be only partially conserved in the mouse. Our data suggest that FGF2 fails to cooperate with SMAD2/3 signaling in actively promoting EpiSC self-renewal through Nanog, in contrast to its role in hESCs. Rather, FGF appears to stabilize the epiblast state by dual inhibition of differentiation to neuroectoderm and of media-induced reversion to a mouse embryonic stem cell-like state. Our data extend the current model of cell fate decisions concerning EpiSCs by clarifying the distinct roles played by FGF signaling.

Graphical AbstractFigure optionsDownload high-quality image (136 K)Download as PowerPoint slideHighlights
► Nanog is a direct target of Activin and SMAD2/3 but not FGF-ERK in EpiSCs
► FGF signaling inhibits neuroectodermal commitment of EpiSCs and hESCs
► FGF inhibition relieves Klf2 repression and reverts EpiSCs to an ESC-like state
► mESCs transition to an EpiSC-like state with LIF inhibition and FGF activation