Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines

Abstract

Embryonic stem cells are established directly from the pluripotent epiblast of the preimplantation mouse embryo. Their derivation and propagation are dependent upon cytokine-stimulated activation of gp130 signal transduction. Embryonic stem cells maintain a close resemblance to epiblast in developmental potency and gene expression profile. The presumption of equivalence between embryonic stem cells and epiblast is challenged, however, by the finding that early embryogenesis can proceed in the absence of gp130. To explore this issue further, we have examined the capacity of gp130 mutant embryos to accommodate perturbation of normal developmental progression. Mouse embryos arrest at the late blastocyst stage when implantation is prevented. This process of diapause occurs naturally in lactating females or can be induced experimentally by removal of the ovaries. We report that gp130−/− embryos survive unimplanted in the uterus after ovariectomy but, in contrast to wild-type or heterozygous embryos, are subsequently unable to resume development. Inner cell masses explanted from gp130−/− delayed blastocysts produce only parietal endoderm, a derivative of the hypoblast. Intact mutant embryos show an absence of epiblast cells, and Hoechst staining and TUNEL analysis reveal a preceding increased incidence of cell death. These findings establish that gp130 signalling is essential for the prolonged maintenance of epiblast in vivo, which is commonly required of mouse embryos in the wild. We propose that the responsiveness of embryonic stem cells to gp130 signalling has its origin in this adaptive physiological function.

Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells

“…For example, leukemia inhibitory factor (LIF), a cytokine that allows maintenance of ES cell pluripotency (Smith et al, 1988;Williams et al, 1988), is dispensable in proliferative blastocysts (Stewart et al, 1992). Although the LIF pathway is not strictly necessary for ES derivation or maintenance in vitro (Ying et al, 2008), knockout of the LIF receptor component gp130 results in loss of the pluripotent epiblast during prolonged diapause (Nichols et al, 2001), providing a clear example of an in vitro pluripotency maintenance factor with physiological roots in diapause. Unraveling diapause networks may thus enable generation of ES cells from species with no established ES cell models.…”

“…Metabolite uptake is also regulated in a stage-specific manner by altered expression of metabolite transporters (Winkle, 2001). During diapause, the embryo stays in close proximity to the uterus and responds to diffusible factors such as LIF (Nichols et al, 2001). The uterine tissue, uterine fluid, and the embryo have been separately studied to identify molecular regulators of diapause.…”

“…For instance, although the cytokine leukemia inhibitory factor (LIF) is expressed in the blastocyst (Nichols et al, 1996), it is dispensable for early embryo development (Stewart et al, 1992). It is, however, required to maintain pluripotency during diapause, as gp130 (LIF receptor component) knock-out embryos lose the epiblast during diapause (Nichols et al, 2001). ES cell pluripotency is alternatively maintained through inhibition of the differentiation-promoting Mek/Erk pathway and enhancement of Wnt pathway activity (Ying et al, 2008).…”

Capturing Pluripotency and Beyond

“…However, like the progressively developing epiblasts in the preimplantation embryo, ESCs still preserve their differentiation capability. Therefore, ESCs share most features with the epiblasts seen in diapause embryos [ 49 ].…”

“…The resultant ESCs share similar characteristics and closely resemble the late preimplantation epiblast, indicating that they are retained at a typical developmental stage characterized by self-renewal in addition to the ability to govern lineage specification [ 79 ]. Although ESCs are in vitro cultured cells, the self-renewal property is unlikely to be an artifact because it can also be observed in the epiblast counterpart of the diapause embryo [ 49 ]. Further evidence showed that self-renewal occurs in the brief period between the late preimplantation embryo and implantation, associated with the concomitant repression of ERK activity [ 21 ].…”