Abstract
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.
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References
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
Agathocleous M, Harris W A (2013). Metabolism in physiological cell proliferation and differentiation. Trends Cell Biol, 23(10): 484–492
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
Bigarella C L, Liang R, Ghaffari S (2014). Stem cells and the impact of ROS signaling. Development, 141(22): 4206–4218
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
Brinster R L, Troike D E (1979). Requirements for blastocyst development in vitro. J Anim Sci, 49(Suppl 2): 26–34
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
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
Carey B W, Finley L W, Cross J R, Allis C D, Thompson C B (2015). Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature, 518(7539): 413–416
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
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
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
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
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
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
Eagle H (1959). Amino acid metabolism in mammalian cell cultures. Science, 130(3373): 432–437
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
Edgar A J (2002). The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. BMC Genet, 3(1): 18
Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156
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
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
Garcia-Gonzalo F R, Izpisúa Belmonte J C (2008). Albumin-associated lipids regulate human embryonic stem cell self-renewal. PLoS ONE, 3(1): e1384
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
Han C, Gu H, Wang J, Lu W, Mei Y, Wu M (2013). Regulation of Lthreonine dehydrogenase in somatic cell reprogramming. Stem Cells, 31(5): 953–965
Hanahan D, Weinberg R A (2011). Hallmarks of cancer: the next generation. Cell, 144(5): 646–674
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
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
Hay N, Sonenberg N (2004). Upstream and downstream of mTOR. Genes Dev, 18(16): 1926–1945
Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K, Nakao M (2012). FADdependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun, 3: 758
Ito K, Suda T (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol, 15(4): 243–256
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
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
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
Kim H, Wu J, Ye S, Tai C I, Zhou X, Yan H, Li P, Pera M, Ying Q L (2013). Modulation of β-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat Commun, 4: 2403
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
Klose R J, Zhang Y (2007). Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol, 8(4): 307–318
Kobayashi H, Kikyo N (2015). Epigenetic regulation of open chromatin in pluripotent stem cells. Transl Res, 165(1): 18–27
Lane A N, Fan T W (2015). Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res, 43(4): 2466–2485
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
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
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
Mathieu J, Zhou W, Xing Y, Sperber H, Ferreccio A, Agoston Z, Kuppusamy K T, Moon R T, Ruohola-Baker H (2014). Hypoxiainducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell, 14(5): 592–605
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
Panopoulos A D, Yanes O, Ruiz S, Kida Y S, Diep D, Tautenhahn R, Herrerías A, Batchelder E M, Plongthongkum N, Lutz M, Berggren WT, 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
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
Prigione A, Rohwer N, Hoffmann S, Mlody B, Drews K, Bukowiecki R, Blümlein K, Wanker E E, Ralser M, Cramer T, Adjaye J (2014). HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2. Stem Cells, 32(2): 364–376
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
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
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
Sharma A, Diecke S, Zhang WY, 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
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
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
Shyh-Chang N, Daley G Q (2015). Metabolic switches linked to pluripotency and embryonic stem cell differentiation. Cell Metab, 21(3): 349–350
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
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-toprimed human embryonic stem cell transition. Nat Cell Biol, 17(12): 1523–1535
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
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
Thomson J A, Odorico J S (2000). Human embryonic stem cell and embryonic germ cell lines. Trends Biotechnol, 18(2): 53–57
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
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
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
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
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
Windmueller H G, Spaeth A E (1974). Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem, 249(16): 5070–5079
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
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
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
Yoon M S, Chen J (2013). Distinct amino acid-sensing mTOR pathways regulate skeletal myogenesis. Mol Biol Cell, 24(23): 3754–3763
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
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 TW (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev, 25(10): 1041–1051
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
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
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
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
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
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). HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J, 31(9): 2103–2116
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Hu, L., Trope, E. & Ying, QL. Metabolism of pluripotent stem cells. Front. Biol. 11, 355–365 (2016). https://doi.org/10.1007/s11515-016-1417-z
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DOI: https://doi.org/10.1007/s11515-016-1417-z