The hematopoietic stem cell diet

Progress in Hematology The regulatory signal for normal and abnormal hematopoiesis

Abstract

Hematopoietic stem cells (HSCs) are responsible for sustaining life-long blood formation or hematopoiesis and are also used clinically in a form of bone marrow transplantation, a curative cellular therapy for a range of hematological diseases. HSCs are maintained throughout adult life by a complex biological niche or microenvironment, which is thought to be composed of a range of cellular, molecular, and metabolic components. The metabolic components of the HSC niche have become of increasing interest over the past few years. It is now well-recognized that metabolic activity is intimately linked to HSC function, and dysregulation of these metabolic pathways result in hematological pathologies such as leukemia. Here, we review the recent progress in this field including our current understanding of the “dietary” requirements of HSCs and how nutrition influences HSC activity. These recent findings have suggested promising new metabolic approaches to improve clinical HSC transplantation and leukemia therapies.

Keywords

Hematopoietic stem cell Metabolism Nutrition HSC Hematopoietic stem cell transplantation Leukemia 

Notes

Acknowledgements

We thank H. J. Beker and other members of the Yamazaki laboratory for feedback on the manuscript. We apologize to those authors whose work could not be cited due to space constraints. SY is supported by the Japan Society for the Promotion of Science (JSPS) (Grant no. 50625580), and the Ministry of Education, Culture, Sport, Science, and Technology (Japan). ACW is supported by Bloodwise (15050) and the NIH National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References

  1. 1.
    Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273(5272):242–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Laurenti E, Göttgens B. From haematopoietic stem cells to complex differentiation landscapes. Nature. 2018;553(7689):418–26.PubMedGoogle Scholar
  3. 3.
    Cheshier SH, Morrison SJ, Liao X, Weissman IL. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA. 1999;96(6):3120–5.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000;192(9):1273–80.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sun J, Ramos A, Chapman B, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yamamoto R, Morita Y, Ooehara J, et al. Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells. Cell. 2013;154(5):1112–26.CrossRefPubMedGoogle Scholar
  7. 7.
    Wilkinson AC, Gottgens B. Transcriptional regulation of haematopoietic stem cells. Adv Exp Med Biol. 2013;786:187–212.CrossRefPubMedGoogle Scholar
  8. 8.
    Wilkinson AC, Nakauchi H, Göttgens B. Mammalian transcription factor networks: recent advances in interrogating biological complexity. Cell Syst. 2017;5(4):319–31.CrossRefPubMedGoogle Scholar
  9. 9.
    Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–34.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood. 2015;125(17):2621–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Eaves CJ. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood. 2015;125(17):2605–13.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354(17):1813–26.CrossRefPubMedGoogle Scholar
  13. 13.
    Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Crane GM, Jeffery E, Morrison SJ. Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017;17(9):573–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Kornberg A. Amino acids in the production of granulocytes in rats. J Biol Chem. 1946;164:203–12.PubMedGoogle Scholar
  16. 16.
    Pietras EM, Warr MR, Passegué E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195(5):709–20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Karigane D, Takubo K. Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions. Int J Hematol. 2017;106(1):18–26.CrossRefPubMedGoogle Scholar
  18. 18.
    Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298–310.CrossRefPubMedGoogle Scholar
  19. 19.
    Takubo K, Goda N, Yamada W, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402.CrossRefPubMedGoogle Scholar
  20. 20.
    Simsek T, Kocabas F, Zheng J, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7(3):380–90.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Takubo K, Nagamatsu G, Kobayashi CI, 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(1):49–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Ito K, Carracedo A, Weiss D, et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med. 2012;18(9):1350–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Signer RA, Magee JA, Salic A, Morrison SJ. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature. 2014;509(7498):49–54.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Taya Y, Ota Y, Wilkinson AC, et al. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation. Science. 2016;354(6316):1152–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Oburoglu L, Tardito S, Fritz V, et al. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell. 2014;15(2):169–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Cabezas-Wallscheid N, Buettner F, Sommerkamp P, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169(5):807–823.e819.CrossRefPubMedGoogle Scholar
  27. 27.
    Cortes M, Chen MJ, Stachura DL, et al. Developmental vitamin D availability impacts hematopoietic stem cell production. Cell Rep. 2016;17(2):458–68.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Studzinski GP, Harrison JS, Wang X, Sarkar S, Kalia V, Danilenko M. Vitamin D control of hematopoietic cell differentiation and leukemia. J Cell Biochem. 2015;116(8):1500–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Agathocleous M, Meacham CE, Burgess RJ, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017;549(7673):476–81.PubMedGoogle Scholar
  30. 30.
    Moran-Crusio K, Reavie L, Shih A, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170(6):1079–1095.e1020.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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(6):725–729.e724.CrossRefPubMedGoogle Scholar
  33. 33.
    Ansó E, Weinberg SE, Diebold LP, et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol. 2017;19(6):614–25.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Luchsinger LL, de Almeida MJ, Corrigan DJ, Mumau M, Snoeck HW. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529(7587):528–31.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ho TT, Warr MR, Adelman ER, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017;543(7644):205–10.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Cao Y, Zhang A, Cai J, et al. Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner. Exp Hematol. 2015;43(3):229–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Ito K, Turcotte R, Cui J, et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016;354(6316):1156–60.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cheng CW, Adams GB, Perin L, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810–23.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lazare S, Ausema A, Reijne AC, van Dijk G, van Os R, de Haan G. Lifelong dietary intervention does not affect hematopoietic stem cell function. Exp Hematol. 2017;53:26–30.CrossRefPubMedGoogle Scholar
  40. 40.
    Ferraro F, Lymperi S, Méndez-Ferrer S, et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med. 2011;3(104):104ra101.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Singer K, DelProposto J, Morris DL, et al. Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells. Mol Metab. 2014;3(6):664–75.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    van den Berg SM, Seijkens TT, Kusters PJ, et al. Diet-induced obesity in mice diminishes hematopoietic stem and progenitor cells in the bone marrow. FASEB J. 2016;30(5):1779–88.CrossRefPubMedGoogle Scholar
  43. 43.
    Li Y, Zhu S, Zhang Y, et al. High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptor γ. Exp Hematol. 2018.  https://doi.org/10.1016/j.exphem.2017.12.013.Google Scholar
  44. 44.
    Ambrosi TH, Scialdone A, Graja A, et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell. 2017;20(6):771–784.e776.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhou BO, Yu H, Yue R, et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol. 2017;19(8):891–903.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Boyd AL, Reid JC, Salci KR, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19(11):1336–47.CrossRefPubMedGoogle Scholar
  47. 47.
    Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Med. 2016;8(1):51.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Luo Y, Chen GL, Hannemann N, et al. Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche. Cell Metab. 2015;22(5):886–94.CrossRefPubMedGoogle Scholar
  49. 49.
    Iwamura C, Bouladoux N, Belkaid Y, Sher A, Jankovic D. Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood. 2017;129(2):171–6.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729–39.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517(7534):302–10.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–76.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374–95.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Meng D, Frank AR, Jewell JL. mTOR signaling in stem and progenitor cells. Development. 2018;145(1):dev152595.CrossRefPubMedGoogle Scholar
  55. 55.
    Ghosh J, Kapur R. Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia. Exp Hematol. 2017;50:13–21.CrossRefPubMedGoogle Scholar
  56. 56.
    Kalaitzidis D, Lee D, Efeyan A, et al. Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Investig. 2017;127(4):1405–13.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    van Galen P, Kreso A, Mbong N, et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature. 2014;510(7504):268–72.CrossRefPubMedGoogle Scholar
  58. 58.
    Domingues MJ, Nilsson SK, Cao B. New agents in HSC mobilization. Int J Hematol. 2017;105(2):141–52.CrossRefPubMedGoogle Scholar
  59. 59.
    Oguro H, McDonald JG, Zhao Z, Umetani M, Shaul PW, Morrison SJ. 27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy. J Clin Investig. 2017;127(9):3392–401.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kumar S, Geiger H. HSC niche biology and HSC expansion ex vivo. Trends Mol Med. 2017;23(9):799–819.CrossRefPubMedGoogle Scholar
  61. 61.
    Guo B, Huang X, Lee MR, Lee SA, Broxmeyer HE. Antagonism of PPAR-γ signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med. 2018;24:360–7.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Longo VD, Cortellino S. Enhancing stem cell transplantation with “nutri-technology”. Cell Stem Cell. 2016;19(6):681–2.CrossRefPubMedGoogle Scholar
  63. 63.
    Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5(4):311–21.CrossRefPubMedGoogle Scholar
  64. 64.
    Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dang L, Su SM. Isocitrate dehydrogenase mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu Rev Biochem. 2017;86:305–31.CrossRefPubMedGoogle Scholar
  66. 66.
    Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care. 2018;21(1):64–70.CrossRefPubMedGoogle Scholar
  68. 68.
    Raffel S, Falcone M, Kneisel N, et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature. 2017;551(7680):384–8.CrossRefPubMedGoogle Scholar
  69. 69.
    Hattori A, Tsunoda M, Konuma T, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 2017;545(7655):500–4.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Lu Z, Xie J, Wu G, et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med. 2017;23(1):79–90.CrossRefPubMedGoogle Scholar
  71. 71.
    Gallipoli P, Giotopoulos G, Tzelepis K, et al. Glutaminolysis is a metabolic dependency in FLT3. Blood. 2018.  https://doi.org/10.1182/blood-2017-12-820035.PubMedGoogle Scholar
  72. 72.
    Samudio I, Harmancey R, Fiegl M, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Investig. 2010;120(1):142–56.CrossRefPubMedGoogle Scholar
  73. 73.
    Koike H, Zhang RR, Ueno Y, et al. Nutritional modulation of mouse and human liver bud growth through a branched-chain amino acid metabolism. Development. 2017;144(6):1018–24.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  1. 1.Institute for Stem Cell Biology and Regenerative MedicineStanford University School of MedicineStanfordUSA
  2. 2.Department of GeneticsStanford UniversityStanfordUSA
  3. 3.Division of Stem Cell Therapy, Institute of Medical ScienceUniversity of TokyoTokyoJapan

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