Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKC-dependent downregulation of HDAC1 and DNMT1/3a

Ryu, Jung Min; Seong, Je Kyung; Han, Ho Jae

doi:10.1080/15384101.2015.1087620

Cited by 19 publications

(20 citation statements)

References 78 publications

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“…In addition, metabolic flux of L-Pro and L-Gln also play key roles in ESC fate including, in particular, through molecular mechanisms that alter the epigenetic landscape at both the histone and DNA levels (Comes et al, 2013;Carey et al, 2015;Ryu et al, 2015). To what extent these mechanisms play a role in improvements in pre-implantation development by L-Pro or L-Gln remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner

Morris¹,

Ozsoy²,

Zada³

et al. 2020

Front. Physiol.

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Groups of amino acids, and some selected amino acids, added to media used for culture of pre-implantation embryos have previously been shown to improve development in various ways including survival to the blastocyst stage, increased blastocyst cell number and improved hatching. In this study, we cultured 1-cell mouse embryos for 5 days to the hatching blastocyst stage in isosmotic medium (270 mOsm/kg) at high density (10 embryos/10 µL), where autocrine/paracrine support of development occurs, and low density (1 embryo/100 µL), where autocrine/paracrine support is minimized and development is compromised. When 400 µM L-Pro or 1 mM L-Gln was added to embryos at low density, the percentage of embryos reaching the blastocyst stage and the percentage hatching increased compared to low-density culture without these amino acids, and were now similar to those for embryos cultured at high density without amino acids. When L-Pro or L-Gln was added to embryos at high density, the percentage of embryos reaching the blastocyst stage didn't change but hatching improved. Neither embryo culture density nor the presence of these amino acids had any effect on blastocyst cell number. D-Pro and the osmolytes Gly and Betaine did not improve embryo development in low-or high-density culture indicating the mechanism was stereospecific and not osmotic, respectively. L-Pro-and L-Glnmediated improvement in development is observed from the 5-cell stage and persists to the blastocyst stage. Molar excess of Gly, Betaine or L-Leu over L-Pro eliminated improvement in development and hatching consistent with them acting as competitive inhibitors of transporter-mediated uptake across the plasma membrane. The L-Pro effect is dependent on mTORC1 signaling (rapamycin sensitive) while that for L-Gln is not. The addition of L-Pro leads to significant nuclear translocation of p-Akt S473 at the 2-and 4-cell stages and of p-ERK1/2 T202/Y204 nuclear translocation at the 2-, 4-, and 8-cell stages. L-Pro improvement in embryo development involves mechanisms analogous to those seen with Pro-mediated differentiation of mouse ES cells, which is also stereoselective, dependent on transporter uptake, and activates Akt, ERK, and mTORC1 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner

Morris¹,

Ozsoy²,

Zada³

et al. 2020

Front. Physiol.

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“…Ryu et al. have reported that Gln is an important factor in regulating maintenance of mouse ESCs through transcription regulation via the Akt, PKCe, and mTOR signalling pathways [ 95 ]; while Krall et al. have revealed that Asn is a powerful regulator of cell amino acid homeostasis; therefore it controls mTOR complex 1 (mTORC1) activation and cellular anabolic metabolism and proliferation [ 91 ].…”

Section: Data Descriptionmentioning

confidence: 99%

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

et al. 2020

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Background Generation of oligodendrocytes is a sophisticated multistep process, the mechanistic underpinnings of which are not fully understood and demand further investigation. To systematically profile proteome dynamics during human embryonic stem cell differentiation into oligodendrocytes, we applied in-depth quantitative proteomics at different developmental stages and monitored changes in protein abundance using a multiplexed tandem mass tag-based proteomics approach. Findings Our proteome data provided a comprehensive protein expression profile that highlighted specific expression clusters based on the protein abundances over the course of human oligodendrocyte lineage differentiation. We identified the eminence of the planar cell polarity signalling and autophagy (particularly macroautophagy) in the progression of oligodendrocyte lineage differentiation—the cooperation of which is assisted by 106 and 77 proteins, respectively, that showed significant expression changes in this differentiation process. Furthermore, differentially expressed protein analysis of the proteome profile of oligodendrocyte lineage cells revealed 378 proteins that were specifically upregulated only in 1 differentiation stage. In addition, comparative pairwise analysis of differentiation stages demonstrated that abundances of 352 proteins differentially changed between consecutive differentiation time points. Conclusions Our study provides a comprehensive systematic proteomics profile of oligodendrocyte lineage cells that can serve as a resource for identifying novel biomarkers from these cells and for indicating numerous proteins that may contribute to regulating the development of myelinating oligodendrocytes and other cells of oligodendrocyte lineage. We showed the importance of planar cell polarity signalling in oligodendrocyte lineage differentiation and revealed the autophagy-related proteins that participate in oligodendrocyte lineage differentiation.

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“…The regulation of desmosomal assembly by DSG1B, DSG2, and PKP1 not only enforces cell surface adhesion contacts between ECs but also regulates the cell signaling events in the cytoplasm and nucleus. DSG2 regulates actin assembly in ECs and affects proliferation via modulation of EGFR signaling [ 43 , 44 ]. PKP1 associates with eukaryotic translation initiation factor 4A1 to stimulate protein translation [ 45 ] and loss of PKP1 is linked to prostate cancer proliferation [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the same study, it was noted that NOTCH blockade modulated the expression of multiple genes regulating glutamate metabolism, including glutaminase and several glutamate transporters [ 55 ]. Tight regulation of glutaminase activity and glutamate metabolism are vital features of both stem cell function and tumor survival [ 11 , 30 , 44 ]. Interestingly, glutamine metabolism also regulates chromatin structure and pluripotency related transcription factors, such as OCT4, and therefore may play a pivotal role in vascular development [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic shift in density-dependent stem cell differentiation

et al. 2017

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BackgroundVascular progenitor cells (VPCs) derived from embryonic stem cells (ESCs) are a valuable source for cell- and tissue-based therapeutic strategies. During the optimization of endothelial cell (EC) inductions from mouse ESCs using our staged and chemically-defined induction methods, we found that cell seeding density but not VEGF treatment between 10 ng/mL and 40 ng/mL was a significant variable directing ESCs into FLK1+ VPCs during stage 1 induction. Here, we examine potential contributions from cell-to-cell signaling or cellular metabolism in the production of VPCs from ESCs seeded at different cell densities.MethodsUsing 1D 1H-NMR spectroscopy, transcriptomic arrays, and flow cytometry, we observed that the density-dependent differentiation of ESCs into FLK1+ VPCs positively correlated with a shift in metabolism and cellular growth.ResultsSpecifically, cell differentiation correlated with an earlier plateauing of exhaustive glycolysis, decreased lactate production, lower metabolite consumption, decreased cellular proliferation and an increase in cell size. In contrast, cells seeded at a lower density of 1,000 cells/cm2 exhibited increased rates of glycolysis, lactate secretion, metabolite utilization, and proliferation over the same induction period. Gene expression analysis indicated that high cell seeding density correlated with up-regulation of several genes including cell adhesion molecules of the notch family (NOTCH1 and NOTCH4) and cadherin family (CDH5) related to vascular development.ConclusionsThese results confirm that a distinct metabolic phenotype correlates with cell differentiation of VPCs.

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Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKC-dependent downregulation of HDAC1 and DNMT1/3a

Cited by 19 publications

References 78 publications

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

Metabolic shift in density-dependent stem cell differentiation

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