Haematopoietic stem cell release is regulated by circadian oscillations

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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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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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) doi:10.1038/nature06685

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