Simplified scheme of signaling pathways required for maintenance of pluripotency of mESC (top panel) and hESC (bottom panel). While both mouse and human ESC require an optimal expression level of Oct4 and Nanog for maintaining pluripotency, the signaling pathways involved in obtaining these optimal expression levels vary significantly in mouse and man. In mESC concomitant LIF and BMP4 signaling are required: LIF causes activation of the JAK/Stat3, MEK/ERK1/2 and PI3K/Akt pathways. JAK/Stat3 signaling is necessary for suppression of differentiation into mesoderm and endoderm. Activation of the PI3K/Akt pathway – apart from being a survival pathway, leads to inhibition of GSK3, resulting in β–catenin translocation to the nucleus and protection of c-myc from degradation, a further mechanism for maintenance of pluripotency. Alternatively this pathway is also activated by canonical Wnt signaling. LIF also activates the MEK/ERK1/2 pathway, which is a differentiation pathway in mESC, and inhibition of various MAPK pathways including the MEK/ERK1/2 pathway is one of the mechanisms by which BMP4 contributes to the maintenance of pluripotency. Concomitantly BMP4 activates the Smad1/5/8 pathway, which inhibits mESC differentiation to neuroectoderm and in combination with Stat3 signaling maintains pluripotency. The Activin pathway described below as important for the pluripotency of hESC, is also necessary for that purpose in mESC, but is provided in an autocrine fashion by the ESC themselves. In contrast, in hESC, FGF2 in combination with Activin, a member of the TGFβ family maintains pluripotency. FGF2 uses at least 3 different signaling cascades for this purpose: 1) It activates the MEK/ERK1/2 pathway, - which is necessary for maintenance of pluripotency in hESC, in contrast to mESC, where this pathway causes differentiation. 2) It inhibits the Smad1/5/8 pathway. Smad1/5/8 activation in hESC causes differentiation, - again opposite effects are seen in mouse and human cells, and 3) FGF2 is known to activate the PI3K/Akt cascade, a pathway contributing to the maintenance of pluripotency in both hESC and mESC. Finally Activin and possibly other TGFβ family members, activate the Smad2/3 pathway, which causes upregulation of Nanog and Oct4 transcription. Nanog prevents neuroectoderm formation induced by FGF2 alone.
