Stem cells and the impact of ROS signaling

An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

[1]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[2]  A. Pyle,et al.  Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. , 2011, Cell stem cell.

[3]  Sathish Kumar Mungamuri,et al.  Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells* , 2008, Journal of Biological Chemistry.

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

[5]  Eric Verdin,et al.  The nexus of chromatin regulation and intermediary metabolism , 2013, Nature.

[6]  N. Pattabiraman,et al.  Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. , 2007, Biochemistry.

[7]  J. Lazo,et al.  Airing out an antioxidant role for the tumor suppressor p53. , 2006, Molecular Interventions.

[8]  Michael P. Myers,et al.  Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate , 2003, Nature.

[9]  Mary F. Lopez,et al.  SOD2-deficiency anemia: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness. , 2004, Blood.

[10]  Young Seok Kim,et al.  Low production of reactive oxygen species and high DNA repair: mechanism of radioresistance of prostate cancer stem cells. , 2013, Anticancer research.

[11]  D. Sinclair,et al.  Mammalian sirtuins: biological insights and disease relevance. , 2010, Annual review of pathology.

[12]  Woojin Jeong,et al.  Reversible Inactivation of the Tumor Suppressor PTEN by H2O2 * , 2002, The Journal of Biological Chemistry.

[13]  Gordon Keller,et al.  Differentiation of Embryonic Stem Cells to Clinically Relevant Populations: Lessons from Embryonic Development , 2008, Cell.

[14]  Yang Liu,et al.  TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species , 2008, The Journal of experimental medicine.

[15]  O. Abdel-Wahab,et al.  Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. , 2011, Cancer cell.

[16]  E. B. Tahara,et al.  Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. , 2009, Free radical biology & medicine.

[17]  V. Ferrans,et al.  Requirement for Generation of H2O2 for Platelet-Derived Growth Factor Signal Transduction , 1995, Science.

[18]  S. Sharkis,et al.  A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. , 2007, Blood.

[19]  S. Morrison,et al.  Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation , 2003, Nature.

[20]  R. Hromas,et al.  Redox Regulation of the Embryonic Stem Cell Transcription Factor Oct‐4 by Thioredoxin , 2004, Stem cells.

[21]  遠山 周吾 Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes , 2013 .

[22]  Andreas Trumpp,et al.  The evolving concept of cancer and metastasis stem cells , 2012, The Journal of cell biology.

[23]  S. Castro-Obregón,et al.  Reactive oxygen species: A radical role in development? , 2010, Free radical biology & medicine.

[24]  B. Ames,et al.  The free radical theory of aging matures. , 1998, Physiological reviews.

[25]  J. Berg,et al.  Dnmt3a is essential for hematopoietic stem cell differentiation , 2011, Nature Genetics.

[26]  T. Kietzmann,et al.  Reactive Oxygen Species Activate the HIF-1&agr; Promoter Via a Functional NF&kgr;B Site , 2007 .

[27]  S. Ghaffari,et al.  Stem cells, redox signaling, and stem cell aging. , 2014, Antioxidants & redox signaling.

[28]  S. Ghaffari,et al.  Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned? , 2011, Current drug targets.

[29]  M. Sigvardsson,et al.  Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. , 2011, Cell stem cell.

[30]  Qingbo Xu,et al.  Embryonic stem cell differentiation into smooth muscle cells is mediated by Nox4-produced H2O2. , 2009, American journal of physiology. Cell physiology.

[31]  T. Finkel Oxidant signals and oxidative stress. , 2003, Current opinion in cell biology.

[32]  John M. Ashton,et al.  Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells* , 2013, The Journal of Biological Chemistry.

[33]  Laurent Vergnes,et al.  UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells , 2011, The EMBO journal.

[34]  Masayuki Yamamoto,et al.  Nrf2-Keap1 defines a physiologically important stress response mechanism. , 2004, Trends in molecular medicine.

[35]  A. Jaiswal,et al.  Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Suematsu,et al.  Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. , 2010, Cell stem cell.

[37]  C. Yabe-Nishimura,et al.  ROS are required for mouse spermatogonial stem cell self-renewal. , 2013, Cell stem cell.

[38]  D. Sinclair,et al.  Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells , 2014, Stem cell reports.

[39]  Andre Terzic,et al.  Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. , 2011, Cell metabolism.

[40]  Hyunjin Cho,et al.  Role of thioredoxin 1 and thioredoxin 2 on proliferation of human adipose tissue-derived mesenchymal stem cells. , 2011, Stem cells and development.

[41]  Hiroshi Handa,et al.  A general mechanism for transcription regulation by Oct1 and Oct4 in response to genotoxic and oxidative stress. , 2009, Genes & development.

[42]  Tak W. Mak,et al.  Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells , 2004, Nature.

[43]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[44]  M. V. Heiden,et al.  Bcl-xL Regulates the Membrane Potential and Volume Homeostasis of Mitochondria , 1997, Cell.

[45]  Sathish Kumar Mungamuri,et al.  ROS‐mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3−/− mice , 2010, The EMBO journal.

[46]  S. Hekimi,et al.  When a theory of aging ages badly , 2009, Cellular and Molecular Life Sciences.

[47]  Mamoru Ito,et al.  Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. , 2011, Blood.

[48]  Yi Zhang,et al.  TET enzymes, TDG and the dynamics of DNA demethylation , 2013, Nature.

[49]  S. Morrison,et al.  Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells , 2010, Nature.

[50]  Jeesun Kim,et al.  Loss of ATM Impairs Proliferation of Neural Stem Cells Through Oxidative Stress‐Mediated p38 MAPK Signaling , 2009, Stem cells.

[51]  A. M. van der Bliek,et al.  Mitochondrial Fission, Fusion, and Stress , 2012, Science.

[52]  G. Daley,et al.  Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. , 2012, Cell stem cell.

[53]  M. Suematsu,et al.  Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. , 2013, Cell stem cell.

[54]  Crispin J. Miller,et al.  Quantitative proteomics reveals posttranslational control as a regulatory factor in primary hematopoietic stem cells. , 2006, Blood.

[55]  R. Colavitti,et al.  This Review Is Part of a Thematic Series on New Paradigms of Transcriptional Control of Myocardial and Vascular Growth, Which Includes the following Articles: Redox-dependent Transcriptional Regulation Excitation-transcription Coupling Redox-dependent Transcriptional Regulation Review Mammalian Redo , 2022 .

[56]  H. Broxmeyer,et al.  Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. , 2013, Cell stem cell.

[57]  C. Robson,et al.  Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding , 1993, Molecular and cellular biology.

[58]  T. Finkel,et al.  Signal transduction by reactive oxygen species , 2011, The Journal of cell biology.

[59]  J. Gribben,et al.  HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. , 2013, Cell stem cell.

[60]  E. Mercken,et al.  Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging , 2013, Cell.

[61]  Ying Guo,et al.  SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization. , 2008, Cell stem cell.

[62]  M. Ushio-Fukai,et al.  Redox regulation of stem/progenitor cells and bone marrow niche. , 2013, Free radical biology & medicine.

[63]  Keisuke Ito,et al.  Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells , 2006, Nature Medicine.

[64]  M. Birnbaum,et al.  AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. , 2010, Blood.

[65]  Michael P. Murphy,et al.  How mitochondria produce reactive oxygen species , 2008, The Biochemical journal.

[66]  Tõnis Org,et al.  The Histone Methyltransferase Activity of MLL1 Is Dispensable for Hematopoiesis and Leukemogenesis , 2014, Cell reports.

[67]  C. Ware,et al.  HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC‐to‐EpiSC/hESC transition , 2012, The EMBO journal.

[68]  D. Sabatini,et al.  Redox Regulation of the Nutrient-sensitive Raptor-mTOR Pathway and Complex* , 2005, Journal of Biological Chemistry.

[69]  Marco Craveiro,et al.  Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. , 2014, Cell stem cell.

[70]  L. Guarente,et al.  The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling , 2013, Cell.

[71]  Y. Lou,et al.  Involvement of p38MAPK and reactive oxygen species in icariin-induced cardiomyocyte differentiation of murine embryonic stem cells in vitro. , 2008, Stem cells and development.

[72]  L. Chin,et al.  FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. , 2009, Cell stem cell.

[73]  Zhaohui Xu,et al.  Functional interaction between FOXO3a and ATM regulates DNA damage response , 2008, Nature Cell Biology.

[74]  K. Kang,et al.  REX-1 Expression and p38 MAPK Activation Status Can Determine Proliferation/Differentiation Fates in Human Mesenchymal Stem Cells , 2010, PloS one.

[75]  J. P. McCoy,et al.  Mitochondrial Metabolism Modulates Differentiation and Teratoma Formation Capacity in Mouse Embryonic Stem Cells* , 2008, Journal of Biological Chemistry.

[76]  H. Broxmeyer,et al.  SIRT1 Positively Regulates Autophagy and Mitochondria Function in Embryonic Stem Cells Under Oxidative Stress , 2014, Stem cells.

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

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

[79]  M. G. Koerkamp,et al.  Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. , 2009, Nature chemical biology.

[80]  U. Banerjee,et al.  Reactive Oxygen Species prime Drosophila haematopoietic progenitors for differentiation , 2009, Nature.

[81]  J. Stamler,et al.  Redox-based regulation of signal transduction: principles, pitfalls, and promises. , 2008, Free radical biology & medicine.

[82]  K. L. de Mesy Bentley,et al.  The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation. , 2011, Developmental cell.

[83]  T. Tuschl,et al.  FOXO1 is an essential regulator of pluripotency in human embryonic stem cells , 2011, Nature Cell Biology.

[84]  John M. Ashton,et al.  BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. , 2013, Cell stem cell.

[85]  L. Chin,et al.  LKB1 regulates quiescence and metabolic homeostasis of hematopoietic stem cells , 2010, Nature.

[86]  Qingbo Xu,et al.  Embryonic stem cell differentiation into smooth muscle cells is mediated by Nox 4-produced H 2 O 2 , 2009 .

[87]  R. Medema,et al.  FOXO4 Is Acetylated upon Peroxide Stress and Deacetylated by the Longevity Protein hSir2SIRT1* , 2004, Journal of Biological Chemistry.

[88]  L. Griffith,et al.  Production of Reactive Oxygen Species by Multipotent Stromal Cells/Mesenchymal Stem Cells upon Exposure to Fas Ligand , 2012, Cell transplantation.

[89]  T. Kietzmann,et al.  Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[90]  R. Weinberg,et al.  hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase , 2001, Cell.

[91]  R. Hammer,et al.  Dependence of Mouse Embryonic Stem Cells on Threonine Catabolism , 2009, Science.

[92]  Steffen Jung,et al.  The ATM–BID pathway regulates quiescence and survival of haematopoietic stem cells , 2012, Nature Cell Biology.

[93]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5- Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1 , 2009 .

[94]  K. Inoki,et al.  Redox Regulates Mammalian Target of Rapamycin Complex 1 (mTORC1) Activity by Modulating the TSC1/TSC2-Rheb GTPase Pathway* , 2011, The Journal of Biological Chemistry.

[95]  Steven P. Gygi,et al.  Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase , 2004, Science.

[96]  W. Dröge Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants , 2002, Experimental Gerontology.

[97]  D. Parks,et al.  Redox state regulates binding of p53 to sequence-specific DNA, but not to non-specific or mismatched DNA. , 1997, Nucleic acids research.

[98]  B. Biteau,et al.  Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. , 2011, Cell stem cell.

[99]  Delin Chen,et al.  Mammalian SIRT1 Represses Forkhead Transcription Factors , 2004, Cell.

[100]  H. Niwa,et al.  A liaison between intrinsic and extrinsic regulators of pluripotency , 2013, The EMBO journal.

[101]  K. Kinzler,et al.  A model for p53-induced apoptosis , 1997, Nature.

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

[103]  Satoshi Tanaka,et al.  Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML , 2010, Nature Biotechnology.

[104]  P. Carmeliet,et al.  Role of PFKFB3-Driven Glycolysis in Vessel Sprouting , 2013, Cell.

[105]  In Hye Lee,et al.  Bmi1 regulates mitochondrial function and the DNA damage response pathway , 2009, Nature.

[106]  C. Nathan,et al.  Beyond oxidative stress: an immunologist's guide to reactive oxygen species , 2013, Nature Reviews Immunology.

[107]  E. Michelakis,et al.  A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation , 2014, Cell.

[108]  J. Eisenbart,et al.  Mitochondrial complex III ROS regulate adipocyte differentiation. , 2011, Cell metabolism.

[109]  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.

[110]  Hui Yang,et al.  Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. , 2012, Genes & development.

[111]  D. Tolan,et al.  Aldolase sequesters WASP and affects WASP/Arp2/3‐stimulated actin dynamics , 2013, Journal of cellular biochemistry.

[112]  S. Henderson,et al.  Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production , 2007, Proceedings of the National Academy of Sciences.

[113]  A. Simpson,et al.  Physiologic oxygen enhances human embryonic stem cell clonal recovery and reduces chromosomal abnormalities. , 2006, Cloning and stem cells.

[114]  Cheng Cheng Zhang,et al.  The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. , 2010, Cell stem cell.

[115]  M. Lavin,et al.  ATM Activation by Oxidative Stress , 2010, Science.

[116]  Rudolf Jaenisch,et al.  Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells , 2009, Nature Biotechnology.

[117]  P. Pandolfi,et al.  A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance , 2012, Nature Medicine.

[118]  H. Ariga,et al.  Mortalin and DJ-1 coordinately regulate hematopoietic stem cell function through the control of oxidative stress. , 2014, Blood.

[119]  A. Terzic,et al.  Metabolic plasticity in stem cell homeostasis and differentiation. , 2012, Cell stem cell.

[120]  S. Armstrong,et al.  FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress , 2007, Cell.

[121]  B. Levi,et al.  Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress , 2010, Nature Cell Biology.

[122]  G. Lozano,et al.  Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity. , 2010, Cell stem cell.

[123]  Francine E. Garrett-Bakelman,et al.  Satb1 regulates hematopoietic stem cell self-renewal by promoting quiescence and repressing differentiation commitment , 2013, Nature Immunology.

[124]  S. Dunwoodie,et al.  Cited2 is required for the maintenance of glycolytic metabolism in adult hematopoietic stem cells. , 2014, Stem cells and development.

[125]  Sunia A Trauger,et al.  Metabolic oxidation regulates embryonic stem cell differentiation , 2010, Nature chemical biology.

[126]  M. Kundu,et al.  Mitophagy in hematopoietic stem cells , 2013, Autophagy.

[127]  Andreas Trumpp,et al.  Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair , 2008, Cell.

[128]  L. Cantley,et al.  FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells , 2013, The EMBO journal.

[129]  Hajime Nakamura,et al.  Glutaredoxin Exerts an Antiapoptotic Effect by Regulating the Redox State of Akt* , 2003, Journal of Biological Chemistry.

[130]  David H Perlman,et al.  Redox regulation of sirtuin-1 by S-glutathiolation. , 2010, Antioxidants & redox signaling.

[131]  D. Harman Free radical theory of aging: dietary implications , 1972 .

[132]  S. Morrison,et al.  Mechanisms that regulate stem cell aging and life span. , 2013, Cell stem cell.

[133]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[134]  G. Sauvageau,et al.  Brief Definitive Report , 2022 .

[135]  Satoko Aratani,et al.  Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[136]  G. Sauvageau,et al.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells , 2003, Nature.

[137]  J. Zweier,et al.  Mitogenic Signaling Mediated by Oxidants in Ras-Transformed Fibroblasts , 1997, Science.

[138]  Massimo Zeviani,et al.  Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. , 2005, Cell metabolism.

[139]  William J. Israelsen,et al.  Cell-State-Specific Metabolic Dependency in Hematopoiesis and Leukemogenesis , 2014, Cell.

[140]  A. Bergman,et al.  Arteriolar niches maintain haematopoietic stem cell quiescence , 2013, Nature.

[141]  Yan-Lin Guo,et al.  Effects of oxidative stress on mouse embryonic stem cell proliferation, apoptosis, senescence, and self-renewal. , 2010, Stem cells and development.

[142]  K. Miyamoto,et al.  Foxo3a is essential for maintenance of the hematopoietic stem cell pool , 2009 .

[143]  G. Gustafsson,et al.  Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. , 2004, Journal of the National Cancer Institute.

[144]  Jing Zhao,et al.  Suppressing phosphatidylcholine‐specific phospholipase C and elevating ROS level, NADPH oxidase activity and Rb level induced neuronal differentiation in mesenchymal stem cells , 2007, Journal of cellular biochemistry.

[145]  Jonathan M Lee,et al.  Inhibition of p53-dependent apoptosis by the KIT tyrosine kinase: regulation of mitochondrial permeability transition and reactive oxygen species generation , 1998, Oncogene.

[146]  Utpal Banerjee,et al.  Mitochondrial Function Controls Proliferation and Early Differentiation Potential of Embryonic Stem Cells , 2011, Stem cells.

[147]  J. McPherson,et al.  Antioxidant Supplementation Reduces Genomic Aberrations in Human Induced Pluripotent Stem Cells , 2014, Stem cell reports.

[148]  M. Yoder,et al.  Ape1 regulates hematopoietic differentiation of embryonic stem cells through its redox functional domain. , 2007, Blood.

[149]  Kohei Miyazono,et al.  Mammalian thioredoxin is a direct inhibitor of apoptosis signal‐regulating kinase (ASK) 1 , 1998, The EMBO journal.

[150]  P. Park,et al.  The Lkb1 metabolic sensor maintains haematopoietic stem cell survival , 2011, Nature.

[151]  Paul T. Schumacker,et al.  Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1 , 2010, Nature.

[152]  S. Orkin,et al.  DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. , 2009, Cell stem cell.

[153]  Alexander A. Morgan,et al.  FoxO3 regulates neural stem cell homeostasis. , 2009, Cell stem cell.

[154]  Chengcheng Zhang,et al.  Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. , 2012, Blood.

[155]  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.

[156]  Steven P Gygi,et al.  Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. , 2005, Nature.

[157]  Jason W. Locasale,et al.  Inhibition of Pyruvate Kinase M2 by Reactive Oxygen Species Contributes to Cellular Antioxidant Responses , 2011, Science.

[158]  B. Jeon,et al.  Redox factor-1: an extra-nuclear role in the regulation of endothelial oxidative stress and apoptosis , 2002, Cell Death and Differentiation.

[159]  Liu Cao,et al.  Oxidants, metabolism, and stem cell biology. , 2011, Free radical biology & medicine.

[160]  T. Finkel,et al.  Cellular mechanisms and physiological consequences of redox-dependent signalling , 2014, Nature Reviews Molecular Cell Biology.

[161]  C. Chen,et al.  SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. , 2005, International journal of molecular medicine.

[162]  Stephanie Xie,et al.  SIRT3 reverses aging-associated degeneration. , 2013, Cell reports.

[163]  Junjie Chen,et al.  Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. , 2010, Molecular cell.

[164]  Jichun Chen,et al.  Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. , 2003, Experimental hematology.

[165]  J. D. Engel,et al.  Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. , 1999, Genes & development.

[166]  James M. Harris,et al.  Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. , 2013, Blood.

[167]  Sathish Kumar Mungamuri,et al.  FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis , 2014, American journal of hematology.

[168]  K. Aldape,et al.  Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation , 2011, Nature.

[169]  Dong Oh Kim,et al.  TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. , 2013, Cell metabolism.

[170]  W. Leonard,et al.  Modulation of transcription factor NF-kappa B binding activity by oxidation-reduction in vitro. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[171]  Koichi Takahashi,et al.  Nrf2 regulates haematopoietic stem cell function , 2013, Nature Cell Biology.

[172]  E. Solary,et al.  A role for reactive oxygen species in JAK2V617F myeloproliferative neoplasm progression , 2013, Leukemia.

[173]  Linda Partridge,et al.  Unraveling the biological roles of reactive oxygen species. , 2011, Cell metabolism.

[174]  N. Chandel,et al.  Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[175]  Yasuhiro Watanabe,et al.  Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. , 2011, Life sciences.

[176]  Irving L. Weissman,et al.  Association of reactive oxygen species levels and radioresistance in cancer stem cells , 2009, Nature.

[177]  Y. Liu,et al.  p53 regulates hematopoietic stem cell quiescence. , 2009, Cell stem cell.