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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (5) : 355-365     DOI: 10.1007/s11515-016-1417-z
Metabolism of pluripotent stem cells
Liang Hu,Edward Trope,Qi-Long Ying()
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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BACKGROUND: Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal of pluripotent stem cells (PSCs), in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome.

OBJECTIVE: To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation.

METHODS: A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used: “metabolism” combined with either “embryonic stem cell” or “epiblast stem cell.”

RESULTS: Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized.

CONCLUSION: Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.

Keywords metabolism      pluripotent stem cells      pluripotency      epigenetics     
Corresponding Authors: Qi-Long Ying   
Online First Date: 13 September 2016    Issue Date: 04 November 2016
 Cite this article:   
Liang Hu,Edward Trope,Qi-Long Ying. Metabolism of pluripotent stem cells[J]. Front. Biol., 2016, 11(5): 355-365.
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Liang Hu
Edward Trope
Qi-Long Ying
Fig.1  The metabolism of glucose in pluripotent stem cells (PSCs). In PSCs, glucose is sequentially catalyzed by multiple enzymes in the cytoplasm to become pyruvate via glycolysis, which can be further oxidized into CO2 in the mitochondrial tricarboxylic acid (TCA) cycle to generate large amounts of ATP through the process of oxidative phosphorylation (OXPHOS) . Pyruvate can also be reductively metabolized to lactate, which predominates in PSCs even under normal oxygen levels. In addition, the metabolism of glucose provides ample intermediates for macromolecule synthesis. For instance, glucose-6-phosphate, glyceraldehyde-3-phosphate, and dihydroxyacetone produced during glucose metabolism can be used to synthesize nucleotides, amino acids, and fatty acids, respectively. NAD: Oxidized nicotinamide adenine dinucleotide; NADH: reduced NAD.
Fig.2  The characteristic amino acid metabolism of PSCs. Under the “2i+LIF” condition, PSCs can convert glutamine into glutamate, which is further rewired to generate a-ketoglutarate (aKG) and thus more aKG-dependent demethylase, such as JmjC dioxygenease. JmjC contributes to pluripotency maintainence through demethylation of the repressive chromatin landscape. In addition, mouse embryonic stem cells (mESCs) are characterized by a unique threonine metabolism. Threonine dehydrogenase (Tdh) converts threonine into glycine and acetyl-CoA. Glycine is then used to produce a one-carbon pool to promote nucleotide synthesis and rapid proliferation of mESCs; Acetyl-coA joins the TCA cycle and feeds the bioenergetics and biosynthetics of mESCs. Furthermore, Tdh enhances the synthesis of S-adenosylmethionine (SAM), leading to a high ratio of SAM/S-adenosyl homocysteine (SAH) and high levels of H3K4me3, an active transcriptional chromatin marker. In contrast, human embryonic stem cells (hESCs) rely on methionine rather than threonine since Tdh is a pseudogene in human. Similar to threonine, methionine is an important source of SAM. Methionine deprivation lowers SAM levels and induces the demethylation of H3K4me3. THF: tetrahydrofolate.
Fig.3  The epigenetic connection between metabolism and pluripotency of PSCs. Cellular metabolism provides ample substrates and co-factors for epigenetic regulation of the genome of PSCs and contributes to pluripotency maintenance. Glucose-derived acetyl-CoA is an important substrate for histone acetylation mediated by histone acetyltransferases (HAT). SAM converted from threonine and methionine is the essential methyl donor for histone methyltransferase (HMT) to maintain proper levels of H3K4me3. In addition, a-ketoglutarate (aKG) from glutamine metabolism activates Jmjd3, an aKG-dependent demethylase, and triggers the demythelyation of repressive chromatin markers. Also, Vitamin C promotes the demethylation of repressive histone markers by enhancing the activity of Tet and JmjC demethylases.
1 Adamo A, Barrero M J, Izpisua Belmonte J C (2011). LSD1 and pluripotency: a new player in the network. Cell Cycle, 10(19): 3215–3216
doi: 10.4161/cc.10.19.17052 pmid: 21926475
2 Agathocleous M, Harris W A (2013). Metabolism in physiological cell proliferation and differentiation. Trends Cell Biol, 23(10): 484–492
doi: 10.1016/j.tcb.2013.05.004 pmid: 23756093
3 Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P (2004). Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem, 279(7): 5288–5297
doi: 10.1074/jbc.M311862200 pmid: 14630918
4 Bigarella C L, Liang R, Ghaffari S (2014). Stem cells and the impact of ROS signaling. Development, 141(22): 4206–4218
doi: 10.1242/dev.107086 pmid: 25371358
5 Blaschke K, Ebata K T, Karimi M M, Zepeda-Martínez J A, Goyal P, Mahapatra S, Tam A, Laird D J, Hirst M, Rao A, Lorincz M C, Ramalho-Santos M (2013). Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature, 500(7461): 222–226
doi: 10.1038/nature12362 pmid: 23812591
6 Brinster R L, Troike D E (1979). Requirements for blastocyst development in vitro. J Anim Sci, 49(Suppl 2): 26–34
pmid: 45481
7 Brons I G, Smithers L E, Trotter M W, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes S M, Howlett S K, Clarkson A, Ahrlund-Richter L, Pedersen R A, Vallier L (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature, 448(7150): 191–195
doi: 10.1038/nature05950 pmid: 17597762
8 Cao Y, Guo W T, Tian S, He X, Wang X W, Liu X, Gu K L, Ma X, Huang D, Hu L, Cai Y, Zhang H, Wang Y, Gao P (2015). miR-290/371-Mbd2-Myc circuit regulates glycolytic metabolism to promote pluripotency. EMBO J, 34(5): 609–623
doi: 10.15252/embj.201490441 pmid: 25603933
9 Carey B W, Finley L W, Cross J R, Allis C D, Thompson C B (2015). Intracellular a-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature, 518(7539): 413–416
doi: 10.1038/nature13981 pmid: 25487152
10 Chen J, Guo L, Zhang L, Wu H, Yang J, Liu H, Wang X, Hu X, Gu T, Zhou Z, Liu J, Liu J, Wu H, Mao S Q, Mo K, Li Y, Lai K, Qi J, Yao H, Pan G, Xu G L, Pei D (2013). Vitamin C modulates TET1 function during somatic cell reprogramming. Nat Genet, 45(12): 1504–1509
doi: 10.1038/ng.2807 pmid: 24162740
11 Cho Y M, Kwon S, Pak Y K, Seol H W, Choi Y M, Park D J, Park K S, Lee H K (2006). Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem Biophys Res Commun, 348(4): 1472–1478
doi: 10.1016/j.bbrc.2006.08.020 pmid: 16920071
12 Comes S, Gagliardi M, Laprano N, Fico A, Cimmino A, Palamidessi A, De Cesare D, De Falco S, Angelini C, Scita G, Patriarca E J, Matarazzo M R, Minchiotti G (2013). L-Proline induces a mesenchymal-like invasive program in embryonic stem cells by remodeling H3K9 and H3K36 methylation. Stem Cell Rep, 1(4): 307–321
doi: 10.1016/j.stemcr.2013.09.001 pmid: 24319666
13 De Bonis M L, Ortega S, Blasco M A (2014). SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells. Stem Cell Rep, 2(5): 690–706
doi: 10.1016/j.stemcr.2014.03.002 pmid: 24936455
14 De Los Angeles A, Ferrari F, Xi R, Fujiwara Y, Benvenisty N, Deng H, Hochedlinger K, Jaenisch R, Lee S, Leitch H G, Lensch M W, Lujan E, Pei D, Rossant J, Wernig M, Park P J, Daley G Q (2015). Hallmarks of pluripotency. Nature, 525(7570): 469–478
doi: 10.1038/nature15515 pmid: 26399828
15 Dunning K R, Cashman K, Russell D L, Thompson J G, Norman R J, Robker R L (2010). Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol Reprod, 83(6): 909–918
doi: 10.1095/biolreprod.110.084145 pmid: 20686180
16 Eagle H (1959). Amino acid metabolism in mammalian cell cultures. Science, 130(3373): 432–437
doi: 10.1126/science.130.3373.432 pmid: 13675766
17 Eagle H, Oyama V I, Levy M, Horton C L, Fleischman R (1956). The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J Biol Chem, 218(2): 607–616
pmid: 13295214
18 Edgar A J (2002). The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. BMC Genet, 3(1): 18
doi: 10.1186/1471-2156-3-18 pmid: 12361482
19 Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156
doi: 10.1038/292154a0 pmid: 7242681
20 Folmes C D, Nelson T J, Martinez-Fernandez A, Arrell D K, Lindor J Z, Dzeja P P, Ikeda Y, Perez-Terzic C, Terzic A (2011). Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab, 14(2): 264–271
doi: 10.1016/j.cmet.2011.06.011 pmid: 21803296
21 Forristal C E, Christensen D R, Chinnery F E, Petruzzelli R, Parry K L, Sanchez-Elsner T, Houghton F D (2013). Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells. PLoS ONE, 8(5): e62507
doi: 10.1371/journal.pone.0062507 pmid: 23671606
22 Garcia-Gonzalo F R, Izpisúa Belmonte J C (2008). Albumin-associated lipids regulate human embryonic stem cell self-renewal. PLoS ONE, 3(1): e1384
doi: 10.1371/journal.pone.0001384 pmid: 18167543
23 Haberland M, Montgomery R L, Olson E N (2009). The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet, 10(1): 32–42
doi: 10.1038/nrg2485 pmid: 19065135
24 Han C, Gu H, Wang J, Lu W, Mei Y, Wu M (2013). Regulation of L-threonine dehydrogenase in somatic cell reprogramming. Stem Cells, 31(5): 953–965
doi: 10.1002/stem.1335 pmid: 23355387
25 Hanahan D, Weinberg R A (2011). Hallmarks of cancer: the next generation. Cell, 144(5): 646–674
doi: 10.1016/j.cell.2011.02.013 pmid: 21376230
26 Hart G W (2014). Three Decades of Research on O-GlcNAcylation- A Major Nutrient Sensor That Regulates Signaling, Transcription and Cellular Metabolism. Front Endocrinol (Lausanne), 5: 183
doi: 10.3389/fendo.2014.00183 pmid: 25386167
27 Hart G W, Slawson C, Ramirez-Correa G, Lagerlof O (2011). Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem, 80(1): 825–858
doi: 10.1146/annurev-biochem-060608-102511 pmid: 21391816
28 Hay N, Sonenberg N (2004). Upstream and downstream of mTOR. Genes Dev, 18(16): 1926–1945
doi: 10.1101/gad.1212704 pmid: 15314020
29 Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K, Nakao M (2012). FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun, 3: 758
doi: 10.1038/ncomms1755 pmid: 22453831
30 Ito K, Suda T (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol, 15(4): 243–256
doi: 10.1038/nrm3772 pmid: 24651542
31 Jang H, Kim T W, Yoon S, Choi S Y, Kang T W, Kim S Y, Kwon Y W, Cho E J, Youn H D (2012). O-GlcNAc regulates pluripotency and reprogramming by directly acting on core components of the pluripotency network. Cell Stem Cell, 11(1): 62–74
doi: 10.1016/j.stem.2012.03.001 pmid: 22608532
32 Kang J X, Wan J B, He C (2014). Concise review: Regulation of stem cell proliferation and differentiation by essential fatty acids and their metabolites. Stem Cells, 32(5): 1092–1098
doi: 10.1002/stem.1620 pmid: 24356924
33 Kim H, Jang H, Kim T W, Kang B H, Lee S E, Jeon Y K, Chung D H, Choi J, Shin J, Cho E J, Youn H D (2015). Core Pluripotency Factors Directly Regulate Metabolism in Embryonic Stem Cell to Maintain Pluripotency. Stem Cells, 33(9): 2699–2711
doi: 10.1002/stem.2073 pmid: 26059508
34 Kim H, Wu J, Ye S, Tai C I, Zhou X, Yan H, Li P, Pera M, Ying Q L (2013). Modulation of b-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat Commun, 4: 2403
doi: 10.1038/ncomms3403 pmid: 23985566
35 Kim J, Chu J, Shen X, Wang J, Orkin S H (2008). An extended transcriptional network for pluripotency of embryonic stem cells. Cell, 132(6): 1049–1061
doi: 10.1016/j.cell.2008.02.039 pmid: 18358816
36 Klose R J, Zhang Y (2007). Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol, 8(4): 307–318
doi: 10.1038/nrm2143 pmid: 17342184
37 Kobayashi H, Kikyo N (2015). Epigenetic regulation of open chromatin in pluripotent stem cells. Transl Res, 165(1): 18–27
doi: 10.1016/j.trsl.2014.03.004 pmid: 24695097
38 Lane A N, Fan T W (2015). Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res, 43(4): 2466–2485
doi: 10.1093/nar/gkv047 pmid: 25628363
39 Lunt S Y, Vander Heiden M G (2011). Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol, 27(1): 441–464
doi: 10.1146/annurev-cellbio-092910-154237 pmid: 21985671
40 Mali P, Chou B K, Yen J, Ye Z, Zou J, Dowey S, Brodsky R A, Ohm J E, Yu W, Baylin S B, Yusa K, Bradley A, Meyers D J, Mukherjee C, Cole P A, Cheng L (2010). Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells, 28(4): 713–720
doi: 10.1002/stem.402 pmid: 20201064
41 Mandal S, Lindgren A G, Srivastava A S, Clark A T, Banerjee U (2011). Mitochondrial function controls proliferation and early differentiation potential of embryonic stem cells. Stem Cells, 29(3): 486–495
doi: 10.1002/stem.590 pmid: 21425411
42 Mathieu J, Zhou W, Xing Y, Sperber H, Ferreccio A, Agoston Z, Kuppusamy K T, Moon R T, Ruohola-Baker H (2014). Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell, 14(5): 592–605
doi: 10.1016/j.stem.2014.02.012 pmid: 24656769
43 Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M, Bomze D, Elena-Herrmann B, Scherf T, Nissim-Rafinia M, Kempa S, Itskovitz-Eldor J, Meshorer E, Aberdam D, Nahmias Y (2015). Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab, 21(3): 392–402
doi: 10.1016/j.cmet.2015.02.002 pmid: 25738455
44 Panopoulos A D, Yanes O, Ruiz S, Kida Y S, Diep D, Tautenhahn R, Herrerías A, Batchelder E M, Plongthongkum N, Lutz M, Berggren W T, Zhang K, Evans R M, Siuzdak G, Izpisua Belmonte J C (2012). The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res, 22(1): 168–177
doi: 10.1038/cr.2011.177 pmid: 22064701
45 Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J (2010). The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells, 28(4): 721–733
doi: 10.1002/stem.404 pmid: 20201066
46 Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blümlein K, Wanker E E, Ralser M, Cramer T, Adjaye J (2014). HIF1a modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells, 32(2): 364–376
doi: 10.1002/stem.1552 pmid: 24123565
47 Ryu J M, Han H J (2011). L-threonine regulates G1/S phase transition of mouse embryonic stem cells via PI3K/Akt, MAPKs, and mTORC pathways. J Biol Chem, 286(27): 23667–23678
doi: 10.1074/jbc.M110.216283 pmid: 21550972
48 Ryu J M, Lee H J, Jung Y H, Lee K H, Kim D I, Kim J Y, Ko S H, Choi G E, Chai I I, Song E J, Oh J Y, Lee S J, Han H J (2015). Regulation of Stem Cell Fate by ROS-mediated Alteration of Metabolism. Int J Stem Cells, 8(1): 24–35
doi: 10.15283/ijsc.2015.8.1.24 pmid: 26019752
49 Segev H, Fishman B, Schulman R, Itskovitz-Eldor J (2012). The expression of the class 1 glucose transporter isoforms in human embryonic stem cells, and the potential use of GLUT2 as a marker for pancreatic progenitor enrichment. Stem Cells Dev, 21(10): 1653–1661
doi: 10.1089/scd.2011.0682 pmid: 22221271
50 Sharma A, Diecke S, Zhang W Y, Lan F, He C, Mordwinkin N M, Chua K F, Wu J C (2013). The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem, 288(25): 18439–18447
doi: 10.1074/jbc.M112.405928 pmid: 23653361
51 Shin J H, Zhang L, Murillo-Sauca O, Kim J, Kohrt H E, Bui J D, Sunwoo J B (2013). Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor. Proc Natl Acad Sci USA, 110(30): 12391–12396
doi: 10.1073/pnas.1302856110 pmid: 23836658
52 Shiraki N, Shiraki Y, Tsuyama T, Obata F, Miura M, Nagae G, Aburatani H, Kume K, Endo F, Kume S (2014). Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab, 19(5): 780–794
doi: 10.1016/j.cmet.2014.03.017 pmid: 24746804
53 Shyh-Chang N, Daley G Q (2015). Metabolic switches linked to pluripotency and embryonic stem cell differentiation. Cell Metab, 21(3): 349–350
doi: 10.1016/j.cmet.2015.02.011 pmid: 25738450
54 Shyh-Chang N, Locasale J W, Lyssiotis C A, Zheng Y, Teo R Y, Ratanasirintrawoot S, Zhang J, Onder T, Unternaehrer J J, Zhu H, Asara J M, Daley G Q, Cantley L C (2013). Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science, 339(6116): 222–226
doi: 10.1126/science.1226603 pmid: 23118012
55 Sperber H, Mathieu J, Wang Y, Ferreccio A, Hesson J, Xu Z, Fischer K A, Devi A, Detraux D, Gu H, Battle S L, Showalter M, Valensisi C, Bielas J H, Ericson N G, Margaretha L, Robitaille A M, Margineantu D, Fiehn O, Hockenbery D, Blau C A, Raftery D, Margolin A A, Hawkins R D, Moon R T, Ware C B, Ruohola-Baker H (2015). The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol, 17(12): 1523–1535
doi: 10.1038/ncb3264 pmid: 26571212
56 Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663–676
doi: 10.1016/j.cell.2006.07.024 pmid: 16904174
57 Takehara T, Teramura T, Onodera Y, Hamanishi C, Fukuda K (2012). Reduced oxygen concentration enhances conversion of embryonic stem cells to epiblast stem cells. Stem Cells Dev, 21(8): 1239–1249
doi: 10.1089/scd.2011.0322 pmid: 21861689
58 Thomson J A, Odorico J S (2000). Human embryonic stem cell and embryonic germ cell lines. Trends Biotechnol, 18(2): 53–57
doi: 10.1016/S0167-7799(99)01410-9 pmid: 10652509
59 Trounson A O, Leeton J F, Wood C, Webb J, Wood J (1981). Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science, 212(4495): 681–682
doi: 10.1126/science.7221557 pmid: 7221556
60 Vozza A, Parisi G, De Leonardis F, Lasorsa F M, Castegna A, Amorese D, Marmo R, Calcagnile V M, Palmieri L, Ricquier D, Paradies E, Scarcia P, Palmieri F, Bouillaud F, Fiermonte G (2014). UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation. Proc Natl Acad Sci USA, 111(3): 960–965
doi: 10.1073/pnas.1317400111 pmid: 24395786
61 Wang J, Alexander P, McKnight S L (2011). Metabolic specialization of mouse embryonic stem cells. Cold Spring Harb Symp Quant Biol, 76(0): 183–193
doi: 10.1101/sqb.2011.76.010835 pmid: 22071264
62 Wang J, Alexander P, Wu L, Hammer R, Cleaver O, McKnight S L (2009). Dependence of mouse embryonic stem cells on threonine catabolism. Science, 325(5939): 435–439
doi: 10.1126/science.1173288 pmid: 19589965
63 Washington J M, Rathjen J, Felquer F, Lonic A, Bettess M D, Hamra N, Semendric L, Tan B S, Lake J A, Keough R A, Morris M B, Rathjen P D (2010). L-Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture. Am J Physiol Cell Physiol, 298(5): C982–C992
doi: 10.1152/ajpcell.00498.2009 pmid: 20164384
64 Windmueller H G, Spaeth A E (1974). Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem, 249(16): 5070–5079
pmid: 4605420
65 Wordinger R J, Kell J A (1978). Elevated glucose levels influence in vitro hatching, attachment, trophoblast outgrowth and differentiation of the mouse blastocyst. Experientia, 34(7): 881–882
doi: 10.1007/BF01939680 pmid: 668859
66 Yanes O, Clark J, Wong D M, Patti G J, Sánchez-Ruiz A, Benton H P, Trauger S A, Desponts C, Ding S, Siuzdak G (2010). Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol, 6(6): 411–417
doi: 10.1038/nchembio.364 pmid: 20436487
67 Ying Q L, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008). The ground state of embryonic stem cell self-renewal. Nature, 453(7194): 519–523
doi: 10.1038/nature06968 pmid: 18497825
68 Yoon M S, Chen J (2013). Distinct amino acid-sensing mTOR pathways regulate skeletal myogenesis. Mol Biol Cell, 24(23): 3754–3763
doi: 10.1091/mbc.E13-06-0353 pmid: 24068326
69 Yoshida Y, Takahashi K, Okita K, Ichisaka T, Yamanaka S (2009). Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell, 5(3): 237–241
doi: 10.1016/j.stem.2009.08.001 pmid: 19716359
70 Zaugg K, Yao Y, Reilly P T, Kannan K, Kiarash R, Mason J, Huang P, Sawyer S K, Fuerth B, Faubert B, Kalliomäki T, Elia A, Luo X, Nadeem V, Bungard D, Yalavarthi S, Growney J D, Wakeham A, Moolani Y, Silvester J, Ten A Y, Bakker W, Tsuchihara K, Berger S L, Hill R P, Jones R G, Tsao M, Robinson M O, Thompson C B, Pan G, Mak T W (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev, 25(10): 1041–1051
doi: 10.1101/gad.1987211 pmid: 21576264
71 Zhang J, Khvorostov I, Hong J S, Oktay Y, Vergnes L, Nuebel E, Wahjudi P N, Setoguchi K, Wang G, Do A, Jung H J, McCaffery J M, Kurland I J, Reue K, Lee W N, Koehler C M, Teitell M A (2011). UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells. EMBO J, 30(24): 4860–4873
doi: 10.1038/emboj.2011.401 pmid: 22085932
72 Zhang J, Nuebel E, Daley G Q, Koehler C M, Teitell M A (2012). Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell, 11(5): 589–595
doi: 10.1016/j.stem.2012.10.005 pmid: 23122286
73 Zhang Z, Xiang D, Wu W S (2014a). Sodium butyrate facilitates reprogramming by derepressing OCT4 transactivity at the promoter of embryonic stem cell-specific miR-302/367 cluster. Cell Reprogram, 16(2): 130–139
doi: 10.1089/cell.2013.0070 pmid: 24568633
74 Zhang Z N, Chung S K, Xu Z, Xu Y (2014b). Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cells, 32(1): 157–165
doi: 10.1002/stem.1532 pmid: 24038750
75 Zhou J, Su P, Wang L, Chen J, Zimmermann M, Genbacev O, Afonja O, Horne M C, Tanaka T, Duan E, Fisher S J, Liao J, Chen J, Wang F (2009). mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. Proc Natl Acad Sci USA, 106(19): 7840–7845
doi: 10.1073/pnas.0901854106 pmid: 19416884
76 Zhou W, Choi M, Margineantu D, Margaretha L, Hesson J, Cavanaugh C, Blau C A, Horwitz M S, Hockenbery D, Ware C, Ruohola-Baker H (2012). HIF1a induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J, 31(9): 2103–2116
doi: 10.1038/emboj.2012.71 pmid: 22446391
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