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Haematopoietic stem cell release is regulated by circadian oscillations

Nature volume 452, pages 442–447 (2008)Cite this article

Abstract

Haematopoietic stem cells (HSCs) circulate in the bloodstream under steady-state conditions, but the mechanisms controlling their physiological trafficking are unknown. Here we show that circulating HSCs and their progenitors exhibit robust circadian fluctuations, peaking 5 h after the initiation of light and reaching a nadir 5 h after darkness. Circadian oscillations are markedly altered when mice are subjected to continuous light or to a ‘jet lag’ (defined as a shift of 12 h). Circulating HSCs and their progenitors fluctuate in antiphase with the expression of the chemokine CXCL12 in the bone marrow microenvironment. The cyclical release of HSCs and expression of Cxcl12 are regulated by core genes of the molecular clock through circadian noradrenaline secretion by the sympathetic nervous system. These adrenergic signals are locally delivered by nerves in the bone marrow, transmitted to stromal cells by the β3-adrenergic receptor, leading to a decreased nuclear content of Sp1 transcription factor and the rapid downregulation of Cxcl12. These data indicate that a circadian, neurally driven release of HSC during the animal’s resting period may promote the regeneration of the stem cell niche and possibly other tissues.

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Figure 1: Circadian traffic of HSCs and their progenitors is entrained by photic input.
Figure 2: Bone marrow Cxcl12 expression oscillates in antiphase with circulating progenitors.
Figure 3: Adrenergic innervation of the bone marrow regulates oscillations in Cxcl12 expression and circulating HSCs.
Figure 4: β 3 -Adrenergic receptor activation decreases Cxcl12 mRNA levels in bone marrow stromal cells and triggers HSC/progenitor mobilization.
Figure 5: The central clock regulates Cxcl12 in bone marrow stromal cells through signals from the sympathetic nervous system.

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References

  1. Goodman, J. W. & Hodgson, G. S. Evidence for stem cells in the peripheral blood of mice. Blood 19, 702–714 (1962)

    CAS  PubMed  Google Scholar 

  2. Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001)

    Article  ADS  CAS  Google Scholar 

  3. Ross, D. D., Pollak, A., Akman, S. A. & Bachur, N. R. Diurnal variation of circulating human myeloid progenitor cells. Exp. Hematol. 8, 954–960 (1980)

    CAS  PubMed  Google Scholar 

  4. Verma, D. S. et al. Diurnal changes in circulating myeloid progenitor cells in man. Am. J. Hematol. 9, 185–192 (1980)

    Article  CAS  Google Scholar 

  5. Lapidot, T. & Petit, I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp. Hematol. 30, 973–981 (2002)

    Article  CAS  Google Scholar 

  6. Mendez-Ferrer, S. & Frenette, P. S. Hematopoietic stem cell trafficking: regulated adhesion and attraction to bone marrow microenvironment. Ann. NY Acad. Sci. 1116, 392–413 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Thomas, J., Liu, F. & Link, D. C. Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor. Curr. Opin. Hematol. 9, 183–189 (2002)

    Article  Google Scholar 

  8. Papayannopoulou, T. Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103, 1580–1585 (2004)

    Article  CAS  Google Scholar 

  9. Levesque, J. P., Hendy, J., Takamatsu, Y., Simmons, P. J. & Bendall, L. J. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J. Clin. Invest. 111, 187–196 (2003)

    Article  CAS  Google Scholar 

  10. Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nature Immunol. 3, 687–694 (2002)

    Article  CAS  Google Scholar 

  11. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem and progenitor cell egress from bone marrow. Cell 124, 407–421 (2006)

    Article  CAS  Google Scholar 

  12. Semerad, C. L. et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106, 3020–3027 (2005)

    Article  CAS  Google Scholar 

  13. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  ADS  CAS  Google Scholar 

  14. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Scadden, D. T. The stem-cell niche as an entity of action. Nature 441, 1075–1079 (2006)

    Article  ADS  CAS  Google Scholar 

  16. Elefteriou, F. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Spiegel, A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nature Immunol. 8, 1123–1131 (2007)

    Article  CAS  Google Scholar 

  18. Arraj, M. & Lemmer, B. Circadian rhythms in heart rate, motility, and body temperature of wild-type C57 and eNOS knock-out mice under light–dark, free-run, and after time zone transition. Chronobiol. Int. 23, 795–812 (2006)

    Article  CAS  Google Scholar 

  19. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000)

    Article  CAS  Google Scholar 

  20. Aiuti, A., Webb, I. J., Bleul, C., Springer, T. & Gutierrez-Ramos, J. C. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J. Exp. Med. 185, 111–120 (1997)

    Article  CAS  Google Scholar 

  21. Wright, D. E., Bowman, E. P., Wagers, A. J., Butcher, E. C. & Weissman, I. L. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J. Exp. Med. 195, 1145–1154 (2002)

    Article  CAS  Google Scholar 

  22. Fu, L., Patel, M. S., Bradley, A., Wagner, E. F. & Karsenty, G. The molecular clock mediates leptin-regulated bone formation. Cell 122, 803–815 (2005)

    Article  CAS  Google Scholar 

  23. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005)

    Article  CAS  Google Scholar 

  24. Frenette, P. S., Subbarao, S., Mazo, I. B., von Andrian, U. H. & Wagner, D. D. Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc. Natl Acad. Sci. USA 95, 14423–14428 (1998)

    Article  ADS  CAS  Google Scholar 

  25. Katayama, Y. et al. PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and α4 integrin. Blood 102, 2060–2067 (2003)

    Article  CAS  Google Scholar 

  26. Katayama, Y., Hidalgo, A., Peired, A. & Frenette, P. S. Integrin α4β7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation. Blood 104, 2020–2026 (2004)

    Article  CAS  Google Scholar 

  27. Maestroni, G. J. et al. Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp. Hematol. 26, 1172–1177 (1998)

    CAS  PubMed  Google Scholar 

  28. Levi, F. & Schibler, U. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593–628 (2007)

    Article  CAS  Google Scholar 

  29. Liu, A. C., Lewis, W. G. & Kay, S. A. Mammalian circadian signaling networks and therapeutic targets. Nature Chem. Biol. 3, 630–639 (2007)

    Article  ADS  CAS  Google Scholar 

  30. Garcia-Moruja, C. et al. Functional characterization of SDF-1 proximal promoter. J. Mol. Biol. 348, 43–62 (2005)

    Article  CAS  Google Scholar 

  31. Rohlff, C., Ahmad, S., Borellini, F., Lei, J. & Glazer, R. I. Modulation of transcription factor Sp1 by cAMP-dependent protein kinase. J. Biol. Chem. 272, 21137–21141 (1997)

    Article  CAS  Google Scholar 

  32. Soeder, K. J. et al. The β3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J. Biol. Chem. 274, 12017–12022 (1999)

    Article  CAS  Google Scholar 

  33. Flierl, M. A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007)

    Article  ADS  CAS  Google Scholar 

  34. Ye, X. & Liu, S. F. Lipopolysaccharide down-regulates Sp1 binding activity by promoting Sp1 protein dephosphorylation and degradation. J. Biol. Chem. 277, 31863–31870 (2002)

    Article  CAS  Google Scholar 

  35. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004)

    Article  CAS  Google Scholar 

  36. Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12–CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006)

    Article  CAS  Google Scholar 

  37. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007)

    Article  CAS  Google Scholar 

  38. Yamazaki, K. & Allen, T. D. Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the ‘neuro-reticular complex’. Am. J. Anat. 187, 261–276 (1990)

    Article  CAS  Google Scholar 

  39. Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007)

    Article  CAS  Google Scholar 

  40. Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001)

    Article  CAS  Google Scholar 

  41. Chruscinski, A. J. et al. Targeted disruption of the β2 adrenergic receptor gene. J. Biol. Chem. 274, 16694–16700 (1999)

    Article  CAS  Google Scholar 

  42. Susulic, V. S. et al. Targeted disruption of the β3-adrenergic receptor gene. J. Biol. Chem. 270, 29483–29492 (1995)

    Article  CAS  Google Scholar 

  43. Dacquin, R., Starbuck, M., Schinke, T. & Karsenty, G. Mouse α1I-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev. Dyn. 224, 245–251 (2002)

    Article  CAS  Google Scholar 

  44. Frenette, P. S., Mayadas, T. N., Rayburn, H., Hynes, R. O. & Wagner, D. D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 84, 563–574 (1996)

    Article  CAS  Google Scholar 

  45. Katayama, Y. & Frenette, P. S. Galactocerebrosides are required postnatally for stromal-dependent bone marrow lymphopoiesis. Immunity 18, 789–800 (2003)

    Article  CAS  Google Scholar 

  46. Wu, X. B. et al. Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J. Clin. Invest. 112, 924–934 (2003)

    Article  CAS  Google Scholar 

  47. Kavurma, M. M., Santiago, F. S., Bonfoco, E. & Khachigian, L. M. Sp1 phosphorylation regulates apoptosis via extracellular FasL–Fas engagement. J. Biol. Chem. 276, 4964–4971 (2001)

    Article  CAS  Google Scholar 

  48. Benestad, H. B., Strom-Gundersen, I., Iversen, P. O., Haug, E. & Nja, A. No neuronal regulation of murine bone marrow function. Blood 91, 1280–1287 (1998)

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. García-Fernández, J. Jang, Y.-S. Ang, P. Tathineni, A. Peired and members of the Frenette Laboratory for their valuable help; M. Zaidi for advice with osteoblast and osteoclast cultures; and I. Lemischka and K. Moore for comments on the manuscript. This work was supported by the National Institutes of Health and the Department of Defense. S.M.-F. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Education and Science. M.B. is supported by a Research Fellowship from the Cooley’s Anemia Foundation. P.S.F. is an Established Investigator of the American Heart Association.

Author Contributions All authors contributed to the design of experiments and analysed data. P.S.F. supervised experiments and wrote the manuscript. S.M.-F. performed circadian measurements of gene expression, circulating progenitors, all Q-PCR, ELISA, in vitro experiments, in vivo effects of adrenergic agonists, immunostainings, western blots and denervation experiments, and prepared figures and wrote the manuscript. D.L. performed circadian progenitor assessments, long-term competitive reconstitutions and 6OHDA experiments. M.B. performed circadian progenitor assessments and G-CSF mobilization experiments.

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Authors and Affiliations

  1. Department of Medicine and Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA,

    Simón Méndez-Ferrer, Daniel Lucas, Michela Battista & Paul S. Frenette

  2. Black Family Stem Cell Institute, New York, New York 10029, USA,

    Paul S. Frenette

  3. Immunology Institute, New York, New York 10029, USA,

    Paul S. Frenette

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  1. Simón Méndez-Ferrer
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Correspondence to Paul S. Frenette.

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Méndez-Ferrer, S., Lucas, D., Battista, M. et al. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008). https://doi.org/10.1038/nature06685

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