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

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.

Amino Acid Transport and Metabolism Regulate Early Embryo Development: Species Differences, Clinical Significance, and Evolutionary Implications

“…While Gln likely functions as an intracellular osmolyte in early embryos under hyperosmotic conditions [4], all we know about other actions of Gln to support preimplantation development is that it does not act through mTOR1 signaling [2]. Beyond the scope of the current discussion, system N is upregulated in the inner cell mass of mouse blastocysts during diapause and is needed there to maintain a diapausing state [29,30]. (See also Section 4.2 below.…”

“…Although the Glu-Gln cycle also produces Glu in the brain, it is insufficient for brain health [95][96][97][98][99]. Similarly, system N for Gln uptake is upregulated in mouse ICM cells to help maintain a diapausing blastocyst state [29,30], but diapause is characterized by a relatively slow cell division in blastocysts. Gln transport into ICM cells must decrease dramatically for the proliferation of ICM cells to continue [29,30], and glutaminase activity is likely relatively low in ES and their progenitor cells [24].…”

“…Similarly, system N for Gln uptake is upregulated in mouse ICM cells to help maintain a diapausing blastocyst state [29,30], but diapause is characterized by a relatively slow cell division in blastocysts. Gln transport into ICM cells must decrease dramatically for the proliferation of ICM cells to continue [29,30], and glutaminase activity is likely relatively low in ES and their progenitor cells [24]. Thus, the conversion of Gln to Glu in ICM cells seems not to be a priority and is unlikely to contribute to the pool of Glu needed to support their pluripotency and proliferation.…”

Perspective: Might Maternal Dietary Monosodium Glutamate (MSG) Consumption Impact Pre- and Peri-Implantation Embryos and Their Subsequent Development?

“…Indeed, glutamate is generated in brain in the glutamate–glutamine cycle, but brain health requires more than this cycle to produce glutamate [ 13 , 14 , 15 , 16 , 17 ]. Moreover, increased glutamine uptake via system N in mouse ICM cells helps maintain diapause in blastocysts [ 18 , 19 ], but cell proliferation is very slow in such blastocysts. Glutamine uptake by ICM cells must be dramatically downregulated to foster their proliferation and break diapause [ 18 , 19 ].…”

“…Moreover, increased glutamine uptake via system N in mouse ICM cells helps maintain diapause in blastocysts [ 18 , 19 ], but cell proliferation is very slow in such blastocysts. Glutamine uptake by ICM cells must be dramatically downregulated to foster their proliferation and break diapause [ 18 , 19 ]. In addition, ES and probably their progenitor cells express relatively low glutaminase activity [ 11 ].…”