Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming.

The bioenergetics of somatic dedifferentiation into induced pluripotent stem cells remains largely unknown. Here, stemness factor-mediated nuclear reprogramming reverted mitochondrial networks into cristae-poor structures. Metabolomic footprinting and fingerprinting distinguished derived pluripotent progeny from parental fibroblasts according to elevated glucose utilization and production of glycolytic end products. Temporal sampling demonstrated glycolytic gene potentiation prior to induction of pluripotent markers. Functional metamorphosis of somatic oxidative phosphorylation into acquired pluripotent glycolytic metabolism conformed to an embryonic-like archetype. Stimulation of glycolysis promoted, while blockade of glycolytic enzyme activity blunted, reprogramming efficiency. Metaboproteomics resolved upregulated glycolytic enzymes and downregulated electron transport chain complex I subunits underlying cell fate determination. Thus, the energetic infrastructure of somatic cells transitions into a required glycolytic metabotype to fuel induction of pluripotency.

[1]  Wenjun Guo,et al.  Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds , 2008, Nature Biotechnology.

[2]  Michael J. Ziller,et al.  Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines , 2011, Cell.

[3]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[4]  W. Gu,et al.  p53 aerobics: the major tumor suppressor fuels your workout. , 2006, Cell metabolism.

[5]  V. Govindaraju,et al.  Proton NMR chemical shifts and coupling constants for brain metabolites , 2000, NMR in biomedicine.

[6]  Timothy J. Nelson,et al.  Induced Pluripotent Reprogramming from Promiscuous Human Stemness‐Related Factors , 2009, Clinical and translational science.

[7]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[8]  David S. Wishart,et al.  HMDB: a knowledgebase for the human metabolome , 2008, Nucleic Acids Res..

[9]  D. K. Arrell,et al.  ATP‐Sensitive K+ Channel‐Deficient Dilated Cardiomyopathy Proteome Remodeled by Embryonic Stem Cell Therapy , 2010, Stem cells.

[10]  A. Terzic,et al.  Developmental Restructuring of the Creatine Kinase System Integrates Mitochondrial Energetics with Stem Cell Cardiogenesis , 2008, Annals of the New York Academy of Sciences.

[11]  Alessandro Vespignani,et al.  ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation , 2009 .

[12]  Andre Terzic,et al.  Induced pluripotent stem cells: developmental biology to regenerative medicine , 2010, Nature Reviews Cardiology.

[13]  R. Roberts,et al.  Low O2 tensions and the prevention of differentiation of hES cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  J. Pelletier,et al.  Target identification using drug affinity responsive target stability (DARTS). , 2009, Proceedings of the National Academy of Sciences of the United States of America.

[15]  H. Schöler,et al.  Induced pluripotent stem cells at nanoscale. , 2010, Stem cells and development.

[16]  Kathrin Plath,et al.  Progress in understanding reprogramming to the induced pluripotent state , 2011, Nature Reviews Genetics.

[17]  D. K. Arrell,et al.  Stem cells transform into a cardiac phenotype with remodeling of the nuclear transport machinery , 2007, Nature Clinical Practice Cardiovascular Medicine.

[18]  Marius Wernig,et al.  Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells , 2007, Nature Biotechnology.

[19]  C. Dang.  The interplay between MYC and HIF in the Warburg effect. , 2007, Ernst Schering Foundation symposium proceedings.

[20]  T. Kirkwood,et al.  Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence , 2007, PLoS biology.

[21]  D. K. Arrell,et al.  Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation. , 2010, Journal of molecular and cellular cardiology.

[22]  Hendrik Neubert,et al.  Label-free detection of differential protein expression by LC/MALDI mass spectrometry. , 2008, Journal of proteome research.

[23]  A. Terzic,et al.  Developmental Enhancement of Adenylate Kinase-AMPK Metabolic Signaling Axis Supports Stem Cell Cardiac Differentiation , 2011, PloS one.

[24]  P. Pedersen,et al.  Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. , 2001, Cancer letters.

[25]  Johan Auwerx,et al.  Histone methyl transferases and demethylases; can they link metabolism and transcription? , 2010, Cell metabolism.

[26]  Andre Terzic,et al.  Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells , 2007, Nature Clinical Practice Cardiovascular Medicine.

[27]  Scott W. Lowe,et al.  Stem cells: The promises and perils of p53 , 2009, Nature.

[28]  M. Blasco,et al.  Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. , 2009, Cell stem cell.

[29]  P. Stacpoole.  The pharmacology of dichloroacetate. , 1989, Metabolism: clinical and experimental.

[30]  G. Schatten,et al.  The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. , 2005, Cloning and stem cells.

[31]  Sheng Ding,et al.  Reprogramming of human primary somatic cells by OCT4 and chemical compounds. , 2010, Cell stem cell.

[32]  Timothy J. Nelson,et al.  iPS Programmed Without c-MYC Yield Proficient Cardiogenesis for Functional Heart Chimerism , 2009, Circulation research.

[33]  S. Egginton,et al.  Mitochondrial DNA replication during differentiation of murine embryonic stem cells , 2007, Journal of Cell Science.

[34]  Hans Lehrach,et al.  The Senescence‐Related Mitochondrial/Oxidative Stress Pathway is Repressed in Human Induced Pluripotent Stem Cells , 2010, Stem cells.

[35]  Sujin Kwon,et al.  Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. , 2006, Biochemical and biophysical research communications.

[36]  G. Prestwich,et al.  Nuclear Magnetic Resonance Metabolomic Footprinting of Human Hepatic Stem Cells and Hepatoblasts Cultured in Hyaluronan‐Matrix Hydrogels , 2008, Stem cells.

[37]  Timothy J. Nelson,et al.  Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. , 2009, Circulation.

[38]  T. Ichisaka,et al.  Hypoxia enhances the generation of induced pluripotent stem cells. , 2009, Cell stem cell.

[39]  T. Ebbels,et al.  Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts , 2007, Nature Protocols.

[40]  D. Beach,et al.  A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. , 2006, Antioxidants & redox signaling.

[41]  M. Stojkovic,et al.  Human Induced Pluripotent Stem Cell Lines Show Stress Defense Mechanisms and Mitochondrial Regulation Similar to Those of Human Embryonic Stem Cells , 2010, Stem cells.

[42]  B. Sykes,et al.  A glycolytic burst drives glucose induction of global histone acetylation by picNuA4 and SAGA , 2009, Nucleic acids research.