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Review
. 2021 Jul 27:9:708318.
doi: 10.3389/fcell.2021.708318. eCollection 2021.

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

Vera A van der Weijden  1 , Aydan Bulut-Karslioglu  1
Affiliations
Review

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

Vera A van der Weijden et al. Front Cell Dev Biol. .

Abstract

The energetically costly mammalian investment in gestation and lactation requires plentiful nutritional sources and thus links the environmental conditions to reproductive success. Flexibility in adjusting developmental timing enhances chances of survival in adverse conditions. Over 130 mammalian species can reversibly pause early embryonic development by switching to a near dormant state that can be sustained for months, a phenomenon called embryonic diapause. Lineage-specific cells are retained during diapause, and they proliferate and differentiate upon activation. Studying diapause thus reveals principles of pluripotency and dormancy and is not only relevant for development, but also for regeneration and cancer. In this review, we focus on the molecular regulation of diapause in early mammalian embryos and relate it to maintenance of potency in stem cells in vitro. Diapause is established and maintained by active rewiring of the embryonic metabolome, epigenome, and gene expression in communication with maternal tissues. Herein, we particularly discuss factors required at distinct stages of diapause to induce, maintain, and terminate dormancy.

Keywords: dormancy; embryonic diapause; metabolism; miRNA; pluripotency; signaling pathways; stem cells; transcription.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Mammalian diapause characteristics in the mouse, roe deer, mink, and wallaby. Embryo morphology, diapause duration, and embryo number differ between species. Diapause duration is independent of the length of post-implantation gestation. Diapause is triggered either seasonally (obligate) or due to lactational stress (facultative). Embryo reactivation is triggered by alterations in photoperiod (mink, wallaby, roe deer) or end of lactation (mouse, wallaby).
FIGURE 2
FIGURE 2
Inducers and features of embryonic diapause. Seasonal variations in photoperiod or lactational stress lead to hormonal alterations. The uterus then fails to establish a receptive state, which blocks implantations and induces diapause. Uterine fluid and extracellular vesicle composition is altered in diapause. The embryo in diapause shows minimal metabolic activity, globally reduced transcription and translation, and diminished or reduced proliferation. Depicted in the figure is a mouse embryo. Parent species where evidence supportive of each statement was derived are shown as icons.
FIGURE 3
FIGURE 3
Hallmarks of the inner cell mass (ICM) of normal and diapause blastocysts. Establishment and maintenance of diapause entails alterations in cellular signaling pathways, transcriptional networks and the chromatin state. The epiblast retains naïve pluripotency during diapause but is polarized due to transient Wnt pathway activity. LIF is required to sustain the epiblast throughout diapause. The transcription-associated histone H4K16 acetylation is depleted in diapause ICM.
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