International Journal of Hematology

, Volume 109, Issue 1, pp 18–27 | Cite as

Metabolism as master of hematopoietic stem cell fate

  • Kyoko Ito
  • Massimo Bonora
  • Keisuke Ito
Progress in Hematology Molecular pathogenesis of leukemia and stem cells


HSCs have a fate choice when they divide; they can self-renew, producing new HSCs, or produce daughter cells that will mature to become committed cells. Technical challenges, however, have long obscured the mechanics of these choices. Advances in flow-sorting have made possible the purification of HSC populations, but available HSC-enriched fractions still include substantial heterogeneity, and single HSCs have proven extremely difficult to track and observe. Advances in single-cell approaches, however, have led to the identification of a highly purified population of hematopoietic stem cells (HSCs) that make a critical contribution to hematopoietic homeostasis through a preference for self-renewing division. Metabolic cues are key regulators of this cell fate choice, and the importance of controlling the population and quality of mitochondria has recently been highlighted to maintain the equilibrium of HSC populations. Leukemic cells also demand tightly regulated metabolism, and shifting the division balance of leukemic cells toward commitment has been considered as a promising therapeutic strategy. A deeper understanding of precisely how specific modes of metabolism control HSC fate is, therefore, of great biological interest, and more importantly will be critical to the development of new therapeutic strategies that target HSC division balance for the treatment of hematological disease.


Cellular metabolism Mitochondria Hematopoietic stem cell Leukemia Stem cell fate 



We are grateful to members of the Ito lab and Einstein Stem Cell Institute for their comments on HSC self-renewal and metabolisms, and most importantly, to the organizing committee and Dr. Masahiro Kizaki for giving us a great opportunity to present our work at JSH 2017. Ke.I. is supported by grants from the National Institutes of Health (R01DK98263, R01DK115577, and R01DK100689), New York State Department of Health as Core Director of Einstein Single-Cell Genomics/Epigenomics (C029154). Ke.I. is a Research Scholar of the Leukemia and Lymphoma Society. We apologize to the investigators whose work could not be cited owing to space limitations.


  1. 1.
    McCulloch EA, Till JE. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res. 1960;13:115–25.Google Scholar
  2. 2.
    Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol. 2001;17:387–403. Scholar
  3. 3.
    Visvader JE, Clevers H. Tissue-specific designs of stem cell hierarchies. Nat Cell Biol. 2016;18:349–55. Scholar
  4. 4.
    Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997;88:287–98.Google Scholar
  5. 5.
    Ramalho-Santos M, Willenbring H. On the origin of the term “stem cell”. Cell Stem Cell. 2007;1:35–8. Scholar
  6. 6.
    Daley GQ, Goodell MA, Snyder EY. Realistic prospects for stem cell therapeutics. Hematol Am Soc Hematol Educ Progr. 2003;2003:398–418.Google Scholar
  7. 7.
    Laurenti E, Gottgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018;553:418–26. Scholar
  8. 8.
    Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science. 1988;241:58–62.Google Scholar
  9. 9.
    Sun J, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514:322–7. Scholar
  10. 10.
    Busch K, et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015;518:542–6. Scholar
  11. 11.
    Sawai CM, et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity. 2016;45:597–609. Scholar
  12. 12.
    Ito K, Frenette PS. HSC contribution in making steady-state blood. Immunity. 2016;45:464–6. Scholar
  13. 13.
    Rodriguez-Fraticelli AE, et al. Clonal analysis of lineage fate in native haematopoiesis. Nature. 2018;553:212–6. Scholar
  14. 14.
    Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med. 2007;357:1472–5. Scholar
  15. 15.
    Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–26. Scholar
  16. 16.
    Ito K, et al. A PML-PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med. 2012;18:1350–8. Scholar
  17. 17.
    Wilson A, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135:1118–29. Scholar
  18. 18.
    Cheng T, et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287:1804–8.Google Scholar
  19. 19.
    Pietras EM, Warr MR, Passegue E. Cell cycle regulation in hematopoietic stem cells. J. Cell Biol. 2011;195:709–20. Scholar
  20. 20.
    Trumpp A, Essers M, Wilson A. Awakening dormant haematopoietic stem cells. Nat. Rev. Immunol. 2010;10:201–9. Scholar
  21. 21.
    Nakamura-Ishizu A, Takizawa H, Suda T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development. 2014;141:4656–66. Scholar
  22. 22.
    Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–34. Scholar
  23. 23.
    Zon LI. Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature. 2008;453:306–13. Scholar
  24. 24.
    Frenette PS, Pinho S, Lucas D, Scheiermann C. Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol. 2013;31:285–316. Scholar
  25. 25.
    Scadden DT. The stem-cell niche as an entity of action. Nature. 2006;441:1075–9. Scholar
  26. 26.
    Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science. 2000;287:1427–30.Google Scholar
  27. 27.
    Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 2014;15:243–56. Scholar
  28. 28.
    Shyh-Chang N, Daley GQ, Cantley LC. Stem cell metabolism in tissue development and aging. Development. 2013;140:2535–47. Scholar
  29. 29.
    Chandel NS, Jasper H, Ho TT, Passegue E. Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol. 2016;18:823–32. Scholar
  30. 30.
    Ito K, Ito K. Metabolism and the control of cell fate decisions and stem cell renewal. Annu Rev Cell Dev Biol. 2016;32:399–409. Scholar
  31. 31.
    Wilkinson AC, Yamazaki S. The hematopoietic stem cell diet. Int J Hematol. 2018. Scholar
  32. 32.
    Anso E, et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol. 2017;19:614–25. Scholar
  33. 33.
    Cabezas-Wallscheid N, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169(819):807–23. e.Google Scholar
  34. 34.
    Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132:631–44. Scholar
  35. 35.
    Woolthuis CM, Park CY. Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage. Blood. 2016;127:1242–8. Scholar
  36. 36.
    Dykstra B, et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell. 2007;1:218–29. Scholar
  37. 37.
    Knapp D, et al. Single-cell analysis identifies a CD33(+) subset of human cord blood cells with high regenerative potential. Nat Cell Biol. 2018;20:710–20. Scholar
  38. 38.
    Carrelha J, et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature. 2018;554:106–11. Scholar
  39. 39.
    Sanjuan-Pla A, et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature. 2013;502:232–6. Scholar
  40. 40.
    Yamamoto R, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154:1112–26. Scholar
  41. 41.
    Yamamoto R, et al. Large-scale clonal analysis resolves aging of the mouse hematopoietic stem cell compartment. Cell Stem Cell. 2018;22:600–7 e604. Scholar
  42. 42.
    Suda T, Suda J, Ogawa M. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci USA. 1984;81:2520–4.Google Scholar
  43. 43.
    Ito K, Ito K. Hematopoietic stem cell fate through metabolic control. Exp Hematol. 2018;64:1–11. Scholar
  44. 44.
    Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273:242–5.Google Scholar
  45. 45.
    Benveniste P, Cantin C, Hyam D, Iscove NN. Hematopoietic stem cells engraft in mice with absolute efficiency. Nat Immunol. 2003;4:708–13. Scholar
  46. 46.
    Gazit R, et al. Fgd5 identifies hematopoietic stem cells in the murine bone marrow. J Exp Med. 2014;211:1315–31. Scholar
  47. 47.
    Acar M, et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature. 2015;526:126–30. Scholar
  48. 48.
    Challen GA, Boles NC, Chambers SM, Goodell MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010;6:265–78. Scholar
  49. 49.
    Chen JY, et al. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature. 2016;530:223–7. Scholar
  50. 50.
    Ito K, et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016;354:1156–60. Scholar
  51. 51.
    Turcotte R, et al. Image-guided transplantation of single cells in the bone marrow of live animals. Sci Rep. 2017;7:3875. Scholar
  52. 52.
    Walter D, et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature. 2015;520:549–52. Scholar
  53. 53.
    Katajisto P, et al. Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science. 2015;348:340–3. Scholar
  54. 54.
    Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14. Scholar
  55. 55.
    Simsek T, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7:380–90. Scholar
  56. 56.
    Takubo K, et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell. 2013;12:49–61. Scholar
  57. 57.
    de Almeida MJ, Luchsinger LL, Corrigan DJ, Williams LJ, Snoeck HW. Dye-independent methods reveal elevated mitochondrial mass in hematopoietic stem cells. Cell Stem Cell. 2017;21(e724):725–9. Scholar
  58. 58.
    Vannini N, et al. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat Commun. 2016;7:13125. Scholar
  59. 59.
    Romero-Moya D, et al. Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function. Haematologica. 2013;98:1022–9. Scholar
  60. 60.
    Gan B, et al. Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010;468:701–4. Scholar
  61. 61.
    Gurumurthy S, et al. The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 2010;468:659–63. Scholar
  62. 62.
    Nakada D, Saunders TL, Morrison SJ. Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature. 2010;468:653–8. Scholar
  63. 63.
    Chen C, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205:2397–408. Scholar
  64. 64.
    Xiao N, et al. Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. Blood. 2012;119:4898–907. Scholar
  65. 65.
    Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9:298–310. Scholar
  66. 66.
    Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell. 2008;132:681–96. Scholar
  67. 67.
    Ito K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51. Scholar
  68. 68.
    Ito K, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431:997–1002. Scholar
  69. 69.
    Miyamoto K, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1:101–12. Scholar
  70. 70.
    Liang R, Ghaffari S, Mitochondria. and FOXO3 in stem cell homeostasis, a window into hematopoietic stem cell fate determination. J Bioenerg Biomembr. 2017;49:343–6. Scholar
  71. 71.
    Testa U, Labbaye C, Castelli G, Pelosi E. Oxidative stress and hypoxia in normal and leukemic stem cells. Exp Hematol. 2016;44:540–60. Scholar
  72. 72.
    Maryanovich M, et al. An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat Commun. 2015;6:7901. Scholar
  73. 73.
    Mohrin M, et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science. 2015;347:1374–7. Scholar
  74. 74.
    Mohrin M, Widjaja A, Liu Y, Luo H, Chen D. The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence. Aging Cell. 2018. Scholar
  75. 75.
    Yu WM, et al. Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell. 2013;12:62–74. Scholar
  76. 76.
    Raffel S, et al. BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature. 2017;551:384–8. Scholar
  77. 77.
    Tefferi A, et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia. 2010;24:1302–9. Scholar
  78. 78.
    Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67. Scholar
  79. 79.
    Agathocleous M, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017;549:476–81. Scholar
  80. 80.
    Cimmino L, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170:1079–95e1020. Scholar
  81. 81.
    Aguilo F, et al. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011;117:5057–66. Scholar
  82. 82.
    Luchsinger LL, de Almeida MJ, Corrigan DJ, Mumau M, Snoeck HW. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529:528–31. Scholar
  83. 83.
    Umemoto T, Hashimoto M, Matsumura T, Nakamura-Ishizu A, Suda T. Ca(2+)-mitochondria axis drives cell division in hematopoietic stem cells. J Exp Med. 2018;215:2097–113. Scholar
  84. 84.
    He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93. Scholar
  85. 85.
    Galluzzi L, Pietrocola F, Levine B, Kroemer G. Metabolic control of autophagy. Cell. 2014;159:1263–76. Scholar
  86. 86.
    Ueno T, Komatsu M. Autophagy in the liver: functions in health and disease. Nat Rev Gastroenterol Hepatol. 2017;14:170–84. Scholar
  87. 87.
    Warr MR, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013;494:323–7. Scholar
  88. 88.
    Doulatov S, et al. Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med. 2017. Scholar
  89. 89.
    Liu F, et al. FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells. Blood. 2010;116:4806–14. Scholar
  90. 90.
    Mortensen M, et al. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci USA. 2010;107:832–7. Scholar
  91. 91.
    Riffelmacher T, Simon AK. Mechanistic roles of autophagy in hematopoietic differentiation. FEBS J. 2017;284:1008–20. Scholar
  92. 92.
    Ho TT, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017;543:205–10. Scholar
  93. 93.
    Jin G, et al. Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. Nat Immunol. 2018;19:29–40. Scholar
  94. 94.
    Zimdahl B, et al. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. Nat Genet. 2014;46:245–52. Scholar
  95. 95.
    Ito T, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature. 2010;466:765–8. Scholar
  96. 96.
    Jaiswal S, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98. Scholar
  97. 97.
    Genovese G, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87. Scholar
  98. 98.
    Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017;17:5–19. Scholar
  99. 99.
    Steensma DP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16. Scholar
  100. 100.
    Papaemmanuil E, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–27. (quiz 3699).Google Scholar
  101. 101.
    Corces MR, Chang HY, Majeti R. Preleukemic hematopoietic stem cells in human acute myeloid leukemia. Front Oncol. 2017;7:263. Scholar
  102. 102.
    Sarkozy C, et al. Outcome of older patients with acute myeloid leukemia in first relapse. Am J Hematol. 2013;88:758–64. Scholar
  103. 103.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.Google Scholar
  104. 104.
    Huntly BJ, Gilliland DG. Cancer biology: summing up cancer stem cells. Nature. 2005;435:1169–70. Scholar
  105. 105.
    Shlush LI, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104–8. Scholar
  106. 106.
    Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441:1068–74. Scholar
  107. 107.
    Kharas MG, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med. 2010;16:903–8. Scholar
  108. 108.
    Wu M, et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell. 2007;1:541–54. Scholar
  109. 109.
    Ward PS, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34. Scholar
  110. 110.
    Garcia-Prat L, Sousa-Victor P, Munoz-Canoves P. Proteostatic and metabolic control of stemness. Cell Stem Cell. 2017;20:593–608. Scholar
  111. 111.
    Jiang Y, Nakada D. Cell intrinsic and extrinsic regulation of leukemia cell metabolism. Int J Hematol. 2016;103:607–16. Scholar
  112. 112.
    Agathocleous M, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017. Scholar
  113. 113.
    Wilkinson AC, Morita M, Nakauchia H, Yamazaki S. Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity. Exp Hematol. 2018;63(11):12–6. e.Google Scholar
  114. 114.
    Hattori A, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 2017;545:500–4. Scholar
  115. 115.
    Sumitomo Y, et al. Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia. Blood. 2016;128:1614–24. Scholar
  116. 116.
    Duarte D, et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell. 2018;22:64–77.e66. Scholar
  117. 117.
    Hawkins ED, et al. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature. 2016;538:518–22. Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  1. 1.Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine ResearchAlbert Einstein College of MedicineBronxUSA
  2. 2.Departments of Cell Biology and MedicineAlbert Einstein College of MedicineBronxUSA
  3. 3.Albert Einstein Cancer Center and Diabetes Research CenterAlbert Einstein College of MedicineBronxUSA

Personalised recommendations