Abstract
Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Nonetheless, ES cells can seemingly acquire TS-like characteristics upon manipulation of lineage-determining transcription factors or activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway. Here we have interrogated the progression of reprogramming in ES cell models with regulatable Oct4 and Cdx2 transgenes or conditional Erk1/2 activation. Although trans-differentiation into TS-like cells is initiated, lineage conversion remains incomplete in all models, underpinned by the failure to demethylate a small group of TS cell genes. Forced expression of these non-reprogrammed genes improves trans-differentiation efficiency, but still fails to confer a stable TS cell phenotype. Thus, even ES cells in ground-state pluripotency cannot fully overcome the boundaries that separate the first cell lineages but retain an epigenetic memory of their ES cell origin.
Highlights
Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers
embryonic stem (ES) cells derived from the inner cell mass (ICM)/epiblast are pluripotent with the capacity to differentiate into all somatic cell types of the adult but are generally excluded from differentiating into trophoblast derivatives; trophoblast stem (TS) cells derived from the TE are committed to a trophoblast cell fate[11,12,13]
To study the progression and fidelity of mouse ES cell trans-differentiation towards the trophoblast lineage, we first focussed on signalling pathways because of their function upstream of transcription factors
Summary
Embryonic (ES) and trophoblast (TS) stem cells reflect the first, irrevocable cell fate decision in development that is reinforced by distinct epigenetic lineage barriers. Cell fate specification is achieved through a close interplay between signalling pathways and transcription factors, leading to a progressive restriction of cellular plasticity that results in terminal differentiation[1,2,3] These differentiation events are accompanied by the acquisition of cell lineage- and cell type-defining epigenetic landscapes that lock in the acquired fate and normally prevent dedifferentiation[2,4]. Numerous elegant embryological and genetic studies have unequivocally shown that by the late-blastocyst stage, commitment to these cell lineages is irreversibly fixed such that TE cells exclusively contribute to extraembryonic trophoblast cell types of the yolk sac and placenta, whereas all somatic cell types of the embryo proper, as well as the germ line, descend from the ICM/epiblast[9,10] This strict cell fate commitment is retained in stem cells that can be derived from the mouse blastocyst. This finding suggested that extracellular signals may directly govern cell fate decisions and be sufficient to induce conversions between established cell lineages
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