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Review
. 2017 Feb 1;144(3):365-373.
doi: 10.1242/dev.142679.

Formative pluripotency: the executive phase in a developmental continuum

Austin Smith  1
Affiliations
Review

Formative pluripotency: the executive phase in a developmental continuum

Austin Smith. Development. .

Abstract

The regulative capability of single cells to give rise to all primary embryonic lineages is termed pluripotency. Observations of fluctuating gene expression and phenotypic heterogeneity in vitro have fostered a conception of pluripotency as an intrinsically metastable and precarious state. However, in the embryo and in defined culture environments the properties of pluripotent cells change in an orderly sequence. Two phases of pluripotency, called naïve and primed, have previously been described. In this Hypothesis article, a third phase, called formative pluripotency, is proposed to exist as part of a developmental continuum between the naïve and primed phases. The formative phase is hypothesised to be enabling for the execution of pluripotency, entailing remodelling of transcriptional, epigenetic, signalling and metabolic networks to constitute multi-lineage competence and responsiveness to specification cues.

Keywords: Developmental potential; Embryonic stem cells; Epiblast; Lineage specification; Pluripotency.

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Conflict of interest statement

Competing interests

The author declares no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Dynamic heterogeneity and phased progression models of pluripotency. (A,B) In the dynamic heterogeneity model of pluripotency (A), naïve and metastable primed cell states co-exist and are interconvertible. Fluctuation between states creates windows of opportunity for commitment. Germline segregation is not well-delineated within this framework. In the phased progression model of pluripotency (B), cells transit sequentially through naïve to formative to primed forms of pluripotency en route to lineage commitment. In the embryo, this process is an orderly continuum. Ex vivo, however, ESCs cultured in serum may comprise all phases simultaneously and the unidirectional developmental order may even be reversed, creating a situation similar to the dynamic heterogeneity model. In both models, culture of mouse ESCs in 2iLIF ground-state conditions constrains pluripotency within the naïve phase. Dashed lines indicate multi-step differentiation, blue shading represents the Oct4-positive pluripotent populations.
Fig. 2.
Fig. 2.
Developmental progression of pluripotency in mouse and human embryos. Pluripotent cells begin to emerge in the ICM and segregate to constitute the naïve epiblast. The multi-coloured cells of the ICM indicate mosaic specification of epiblast and hypoblast. After implantation in both mouse (E5) and human (day 8) embryos the epiblast expands as a pseudoepithelial layer overlying the hypoblast (also called the extra-embryonic endoderm), forming a cup-shaped cylinder in mice and a disc in humans. During this period, epiblast cells may remain unpatterned and without molecular specification. Subsequently, epiblast cells become fixed in a columnar epithelium, display regionalised expression of specification factors in response to extra-embryonic signalling centres, and initiate gastrulation. This sequence of events is reflected in transcriptional and epigenetic changes. The distinction between naïve pluripotency and the hypothesised formative phase appears to be acute, whereas the subsequent transition to primed pluripotency is more gradual. Formative and primed phases may be present together at the early stages of gastrulation, particularly in humans. Epi, epiblast; Hyp, hypoblast.
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References

    1. Acampora D., Di Giovannantonio L. G. and Simeone A. (2013). Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition. Development 140, 43-55. 10.1242/dev.085290 - DOI - PubMed
    1. Acampora D., Omodei D., Petrosino G., Garofalo A., Savarese M., Nigro V., Di Giovannantonio L. G., Mercadante V. and Simeone A. (2016). Loss of the Otx2-binding site in the nanog promoter affects the integrity of embryonic stem cell subtypes and specification of inner cell mass-derived epiblast. Cell Rep. 15, 2651-2664. 10.1016/j.celrep.2016.05.041 - DOI - PubMed
    1. Auclair G., Guibert S., Bender A. and Weber M. (2014). Ontogeny of CpG island methylation and specificity of DNMT3 methyltransferases during embryonic development in the mouse. Genome Biol. 15, 545 10.1186/s13059-014-0545-5 - DOI - PMC - PubMed
    1. Bao S., Tang F., Li X., Hayashi K., Gillich A., Lao K. and Surani M. A. (2009). Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292-1295. 10.1038/nature08534 - DOI - PMC - PubMed
    1. Beddington R. S. (1983). Histogenetic and neoplastic potential of different regions of the mouse embryonic egg cylinder. J. Embryol. Exp. Morphol. 75, 189-204. - PubMed

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