Extracellular Signalling and Stem Cell Self-Renewal

Wamaitha, Sissy E. (2017). Extracellular Signalling and Stem Cell Self-Renewal. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000c596


In preimplantation mouse embryos, signalling and gene regulatory networks cooperate to determine lineage segregation, and modulating signalling in vitro allows for stem cell populations to be established from these lineages. Fibroblast growth factor (FGF) signalling triggers the differentiation of primitive endoderm (PrE) cells fated to contribute to the yolk sac, while cells unreceptive to FGF form the epiblast (Epi) that subsequently contributes to the embryo proper. In vitro, FGF signalling is required for preimplantation Epi-derived mouse ES cells to exit self-renewal. Conversely, in human ES cells and postimplantation Epi-derived mouse epiblast stem cells, FGF signalling is instead required for pluripotency maintenance. It remains unclear how these divergent outcomes arise, especially as these cells rely on a similar core pluripotency gene network.

This study demonstrates that ectopic expression of the PrE transcription factor Gata6 destabilises mouse ES cell pluripotency in vitro and upregulates PrE-associated genes independently of FGF signalling. As previous studies show that PrE specification is compromised in Fgf4-/- embryos, despite initiation of Gata6, this suggests FGF signalling and Gata6 cooperatively drive PrE specification in vivo. Characterising Gata6 function determines that it directly binds to both up- and downregulated gene targets and potently initiates reprogramming in multiple cell types, including human ES cells, suggesting it may also antagonise pluripotency in vivo.

Surprisingly, FGF stimulation negatively affects establishment of the pluripotent human Epi. Characterising alternative signalling pathways in the human embryo finds that modulating IGF signalling promotes proliferation of the human ICM, and similar to human ES cells, intact TGFβ/Nodal signalling is required for pluripotent gene expression in the Epi. Consequently, as signalling requirements in the human Epi appear somewhat distinct from both the mouse Epi and existing human ES cells, modulating embryo-specific signalling pathways may permit derivation of human ES cells that more accurately reflect the pluripotent Epi compartment.

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