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Cited by 671Pluripotent Stem Cells ResearchCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts

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Varum, Sandra, Rodrigues, Ana S., Moura, Michelle B., Momcilovic, Olga, Easley, Charles A., Ramalho-Santos, João, Van Houten, Bennett, Schatten, Gerald·2011·PLoS ONE
DOI 10.1371/journal.pone.0020914PMC PMC3117868
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Abstract

BACKGROUND: Human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell-based therapies. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Interestingly, many cancer types have been reported to display metabolic modifications with features that might be similar to stem cells. Understanding the metabolic properties of human pluripotent stem cells when compared to their differentiated counterparts can thus be of crucial importance. Furthermore recent data has stressed distinct features of different human pluripotent cells lines, namely when comparing embryo-derived human embryonic stem cells (hESCs) and induced pluripotent stem cells (IPSCs) reprogrammed from somatic cells. METHODOLOGY/PRINCIPAL FINDINGS: We compared the energy metabolism of hESCs, IPSCs, and their somatic counterparts. Focusing on mitochondria, we tracked organelle localization and morphology. Furthermore we performed gene expression analysis of several pathways related to the glucose metabolism, including glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle. In addition we determined oxygen consumption rates (OCR) using a metabolic extracellular flux analyzer, as well as total intracellular ATP levels by high performance liquid chromatography (HPLC). Finally we explored the expression of key proteins involved in the regulation of glucose metabolism. CONCLUSIONS/FINDINGS: Our results demonstrate that, although the metabolic signature of IPSCs is not identical to that of hESCs, nonetheless they cluster with hESCs rather than with their somatic counterparts. ATP levels, lactate production and OCR revealed that human pluripotent cells rely mostly on glycolysis to meet their energy demands. Furthermore, our work points to some of the strategies which human pluripotent stem cells may use to maintain high glycolytic rates, such as high levels of hexokinase II and inactive pyruvate dehydrogenase (PDH).

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  1. [1]Yu J Vodyanik MA Smuga-Otto K Antosiewicz-Bourget J Frane JL 2007 Induced pluripotent stem cell lines derived from human somatic cells. Science 318 1917 1920 18029452
  2. [3]Takahashi K Tanabe K Ohnuki M Narita M Ichisaka T 2007 Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131 861 872 18035408
  3. [4]Chin MH Mason MJ Xie W Volinia S Singer M 2009 Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5 111 123 19570518 PMC3448781
  4. [5]Maherali N Sridharan R Xie W Utikal J Eminli S 2007 Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1 55 70 18371336
  5. [6]Doi A Park IH Wen B Murakami P Aryee MJ 2009 Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41 1350 1353 19881528 PMC2958040
  6. [7]Hawkins RD Hon GC Lee LK Ngo Q Lister R 2010 Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 6 479 491 20452322 PMC2867844
  7. [8]Deng J Shoemaker R Xie B Gore A LeProust EM 2009 Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27 353 360 19330000 PMC2715272
  8. [9]Lister R Pelizzola M Kida YS Hawkins RD Nery JR 2011 Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471 68 73 21289626 PMC3100360
  9. [10]Bock C Kiskinis E Verstappen G Gu H Boulting G 2011 Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144 439 452 21295703 PMC3063454
  10. [11]Hussein SM Batada NN Vuoristo S Ching RW Autio R 2011 Copy number variation and selection during reprogramming to pluripotency. Nature 471 58 62 21368824
  11. [12]Fischer B Bavister BD 1993 Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J Reprod Fertil 99 673 679 8107053
  12. [13]Gore A Li Z Fung HL Young JE Agarwal S 2011 Somatic coding mutations in human induced pluripotent stem cells. Nature 471 63 67 21368825 PMC3074107
  13. [14]Zhao T Zhang ZN Rong Z Xu Y 2011 Immunogenicity of induced pluripotent stem cells. Nature 21572395
  14. [15]Leese HJ Barton AM 1984 Pyruvate and glucose uptake by mouse ova and preimplantation embryos. J Reprod Fertil 72 9 13 6540809
  15. [16]Ramalho-Santos J Varum S Amaral S Mota PC Sousa AP 2009 Mitochondrial functionality in reproduction: from gonads and gametes to embryos and embryonic stem cells. Hum Reprod Update 15 553 572 19414527
  16. [17]Stern S Biggers JD Anderson E 1971 Mitochondria and early development of the mouse. J Exp Zool 176 179 191 5559227
  17. [18]Houghton FD 2006 Energy metabolism of the inner cell mass and trophectoderm of the mouse blastocyst. Differentiation 74 11 18 16466396
  18. [19]St John JC Ramalho-Santos J Gray HL Petrosko P Rawe VY 2005 The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Cloning Stem Cells 7 141 153 16176124
  19. [20]Cho YM Kwon S Pak YK Seol HW Choi YM 2006 Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem Biophys Res Commun 348 1472 1478 16920071
  20. [21]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 28 721 733 20201066
  21. [22]Ezashi T Das P Roberts RM 2005 Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci U S A 102 4783 4788 15772165 PMC554750
  22. [23]Forristal CE Wright KL Hanley NA Oreffo RO Houghton FD 2010 Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction 139 85 97 19755485 PMC2791494
  23. [24]Yoshida Y Takahashi K Okita K Ichisaka T Yamanaka S 2009 Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5 237 241 19716359
  24. [25]Semenza GL 2007 Life with oxygen. Science 318 62 64 17916722
  25. [26]Bustamante E Pedersen PL 1977 High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci U S A 74 3735 3739 198801 PMC431708
  26. [27]Bustamante E Morris HP Pedersen PL 1981 Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 256 8699 8704 7263678
  27. [28]Holness MJ Sugden MC 2003 Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31 1143 1151 14641014
  28. [29]Roche TE Hiromasa Y 2007 Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 64 830 849 17310282 PMC11136253
  29. [30]Ferreira LM 2010 Cancer metabolism: the Warburg effect today. Exp Mol Pathol 89 372 380 20804748
  30. [31]Yeung TM Gandhi SC Bodmer WF 2011 Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci U S A 108 4382 4387 21368208 PMC3060223
  31. [32]Madhok BM Yeluri S Perry SL Hughes TA Jayne DG 2010 Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer 102 1746 1752 20485289 PMC2883702
  32. [33]Loiseau D Morvan D Chevrollier A Demidem A Douay O 2009 Mitochondrial bioenergetic background confers a survival advantage to HepG2 cells in response to chemotherapy. Mol Carcinog 48 733 741 19347860
  33. [34]Jose C Bellance N Rossignol R 2010 Choosing between glycolysis and oxidative phosphorylation: A tumor's dilemma? Biochim Biophys Acta 20955683
  34. [35]Varum S Momcilovic O Castro C Ben-Yehudah A Ramalho-Santos J 2009 Enhancement of human embryonic stem cell pluripotency through inhibition of the mitochondrial respiratory chain. Stem Cell Res 3 142 156 19716358 PMC2837416
  35. [36]Wieckowski MR Giorgi C Lebiedzinska M Duszynski J Pinton P 2009 Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc 4 1582 1590 19816421
  36. [37]Qian W Van Houten B 2010 Alterations in bioenergetics due to changes in mitochondrial DNA copy number. Methods 51 452 457 20347038
  37. [38]Lambert AJ Brand MD 2004 Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem 279 39414 39420 15262965
  38. [39]Arora KK Pedersen PL 1988 Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem 263 17422 17428 3182854
  39. [40]Mathupala SP Ko YH Pedersen PL 2009 Hexokinase-2 bound to mitochondria: cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy. Semin Cancer Biol 19 17 24 19101634 PMC2714668
  40. [41]Wamelink MM Struys EA Huck JH Roos B van der Knaap MS 2005 Quantification of sugar phosphate intermediates of the pentose phosphate pathway by LC-MS/MS: application to two new inherited defects of metabolism. J Chromatogr B Analyt Technol Biomed Life Sci 823 18 25 16055050
  41. [42]Kletzien RF Harris PK Foellmi LA 1994 Glucose-6-phosphate dehydrogenase: a "housekeeping" enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stress. FASEB J 8 174 181 8119488
  42. [43]Tian WN Braunstein LD Pang J Stuhlmeier KM Xi QC 1998 Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J Biol Chem 273 10609 10617 9553122
  43. [44]Boros LG Torday JS Lim S Bassilian S Cascante M 2000 Transforming growth factor beta2 promotes glucose carbon incorporation into nucleic acid ribose through the nonoxidative pentose cycle in lung epithelial carcinoma cells. Cancer Res 60 1183 1185 10728670
  44. [45]Cascante M Centelles JJ Veech RL Lee WN Boros LG 2000 Role of thiamin (vitamin B-1) and transketolase in tumor cell proliferation. Nutr Cancer 36 150 154 10890024
  45. [46]Kim JW Zeller KI Wang Y Jegga AG Aronow BJ 2004 Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 24 5923 5936 15199147 PMC480875
  46. [47]Gordan JD Thompson CB Simon MC 2007 HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12 108 113 17692803 PMC3215289
  47. [48]Li F Wang Y Zeller KI Potter JJ Wonsey DR 2005 Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25 6225 6234 15988031 PMC1168798
  48. [49]Wu KJ Polack A Dalla-Favera R 1999 Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 283 676 679 9924025
  49. [50]Adams FH Yanagisawa M Kuzela D Martinek H 1971 The disappearance of fetal lung fluid following birth. J Pediatr 78 837 843 5581589
  50. [51]Cinelli P Casanova EA Uhlig S Lochmatter P Matsuda T 2008 Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3. BMC Dev Biol 8 57 18500982 PMC2409313
  51. [52]Heikkinen S Pietila M Halmekyto M Suppola S Pirinen E 1999 Hexokinase II-deficient mice. Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. J Biol Chem 274 22517 22523 10428828
  52. [53]Golshani-Hebroni SG Bessman SP 1997 Hexokinase binding to mitochondria: a basis for proliferative energy metabolism. J Bioenerg Biomembr 29 331 338 9387093
  53. [54]Majewski N Nogueira V Robey RB Hay N 2004 Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol 24 730 740 14701745 PMC343797
  54. [55]Coussens M Davy P Brown L Foster C Andrews WH 2010 RNAi screen for telomerase reverse transcriptase transcriptional regulators identifies HIF1alpha as critical for telomerase function in murine embryonic stem cells. Proc Natl Acad Sci U S A 107 13842 13847 20643931 PMC2922273
  55. [56]Berridge MV Herst PM Tan AS 2010 Metabolic flexibility and cell hierarchy in metastatic cancer. Mitochondrion 10 584 588 20709626
  56. [57]Suhr ST Chang EA Tjong J Alcasid N Perkins GA 2010 Mitochondrial rejuvenation after induced pluripotency. PLoS One 5 e14095 21124794 PMC2991355

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Authors
Varum, S., Rodrigues, A. S., Moura, M. B., Momcilovic, O., Easley, C. A., Ramalho-Santos, J., Van Houten, B., & Schatten, G.
Affiliations
  • Magee-Womens Research Institute (US)
  • University of Pittsburgh (US)
Corresponding author
Schatten, Gerald
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-06-17
Volume
6
Issue
6
Pages
e20914
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0020914
PMC
PMC3117868
OpenAlex
W2025192477
Cited by
671
References
1
Citations by year
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FWCI
16.33
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (5p01hd047675-05)
  • Fundação para a Ciência e a Tecnologia (PTDC/EBB-EBI/101114/2008, SFRH/BD/33463/2008)
  • National Institute of Environmental Health Sciences (R01ES019566)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01-HD047675, 1P01HD047675)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
human pluripotent stem cells, energy metabolism, human embryonic stem cells, induced pluripotent stem cells, glucose metabolism, glycolysis, mitochondrial morphology, oxygen consumption rate, ATP levels, lactic acid production, hexokinase 2, pyruvate dehydrogenase, pentose phosphate pathway, TCA cycle, cancer metabolism
MeSH terms
Cell Differentiation, Cell Line, Chromatography, High Pressure Liquid, Energy Metabolism, Humans, Immunohistochemistry, Mitochondria, Oxidative Phosphorylation, Oxygen Consumption, Transduction, Genetic, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Pluripotent Stem Cells

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