Haematopoietic stem cell release is regulated by circadian oscillations.
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 beta(3)-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.
Méndez-Ferrer
Simón
S
Mount Sinai School of Medicine, Department of Medicine and Department of Gene and Cell Medicine, New York, New York 10029, USA.
Lucas
Daniel
D
Battista
Michela
M
Frenette
Paul S
PS
D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D001853:Bone Marrow / Q000294:innervation* / Q000378:metabolism / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000378:metabolism / Q000528:radiation effects; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology* / Q000528:radiation effects; D003463:Cues; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts; D010775:Photic Stimulation; D022702:Receptors, Adrenergic, beta-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000528:radiation effects
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D022702:Receptors, Adrenergic, beta-3; D016329:Sp1 Transcription Factor