Comparative analysis of the mitochondrial morphology, energy metabolism, and gene expression signatures in three types of blastocyst-derived stem cells

Lactate Accelerates Mouse ES Cell Differentiation Towards the XEN Lineage

“…ES colony shape appeared to be insensitive to 2-DG and oligomycin treatment; however, XEN cells lost their distinct morphologies, particularly in the 2-DG treatment and adopted a spindle-like morphology, indicative of cell stress (Figure 1A). In contrast to a previous report (Choi et al, 2020), XEN cells were more sensitive to glycolytic inhibition (5.87% ± 1.82) than OXPHOS inhibition with oligomycin (41.3% ± 7.30; P < 0.01; Figure 1B). Since ES cells are metabolically bivalent (Zhou et al, 2012), the significant reduction in cell viability under both treatments was expected ( P < 0.01) and not significant between the two treatments (2-DG: 45.3% ± 8.84 versus oligomycin: 62.7% ± 5.24; Figure 1B).…”

“…In contrast, 1716 genes ( Figure 3A) and 298 proteins ( Figure 3B) were significantly upregulated in XEN cells. As expected, markers of pluripotency including Nanog, Sox2, OCT4 and ESRRB were enriched in the ES population, while XEN markers such as Gata4/6, Sox7/17, Dab2, and PDGFRA were significantly enriched in XEN cells ( Figure 3A Figure 3F, G, S3G, H), as reported previously (Choi et al, 2020). However, metabolism of xenobiotics by cytochrome P450 and glucose/pyruvate metabolism were enriched in the ES population and represent two common KEGG pathways between the RNAseq and MS datasets ( Figure 3C, D).…”

“…A recent report characterized the metabolic profile of XEN cells as reliant on OXPHOS metabolism (Choi et al, 2020). Albeit informative, this study derived and maintained XEN cells on inactivated mouse embryonic fibroblasts, which are oxidative in nature (Folmes et al, 2011) and are known to reduce the reliance of pluripotent stem cells on glycolysis (Gu et al, 2016).…”

“…We have shown previously that F9 embryonal carcinoma cells mimic the transition to a XEN-like lineage when co-treated with retinoic acid and a cAMP analog, and more importantly, these cells exhibited a metabolic phenotype reliant exclusively on glycolysis (Gatie and Kelly, 2018). While recent reports have expanded on the metabolic profiles observed in the early embryonic lineages (Choi et al, 2020;Zhou et al, 2012 parietal endoderm cells interact with trophoblast stem cells and undergo an epithelial-tomesenchymal transition and migrate along the inner surface of the trophectoderm (Hogan et al, 1980). Therefore, the precise identity of these XEN cells and their interaction with the microenvironment may influence their metabolic needs.…”

“…Naïve ES cells exhibit a bivalent metabolic profile, relying on glycolysis and oxidative phosphorylation (OXPHOS) to generate energy, while epiblast stem cells are exclusively glycolytic, despite displaying a mature mitochondrial ultrastructure (Zhou et al, 2012). Although the majority of studies have focused on naïve and primed ES cells, recent reports on extraembryonic cells show they are reliant on OXPHOS metabolism (Choi et al, 2020), with a similar mitochondrial ultrastructure to epiblast stem cells (Seo et al, 2020; Zhou et al, 2012). However, details on the comprehensive intracellular profile of metabolites and their role during differentiation remains unknown.…”