Journal Article

Haematopoietic stem cell release is regulated by circadian oscillations

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

2008

Overview

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 β 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. Stem cells got rhythm Haematopoietic stem cells (HSCs) circulate in the blood, where they can home to sites throughout the body. The release of these cells into the blood stream has now been found to be regulated by circadian rhythms. In mice, HSCs undergo pronounced fluctuations corresponding to circadian oscillations induced by continuous light or by a 12-hour time-shift or 'jet lag'. Timing of the expression of the chemokine CXCL12 in the stem cell niche was also in step with the oscillations in response to adrenergic signals delivered locally by nerves in the bone marrow. The rhythmic release of stem cells into the blood during the animal's resting period suggests a possible role in regeneration. Circulating haematopoetic stem cells and their progenitors exhibit robust circadian fluctuations, peaking 5 hours after the initiation of light and reaching a nadir 5 hours 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). Data also suggests that circadian, neurally driven haematopoetic stem cells release during the animal's resting period may promote regeneration of the stem cell niche, and possibly of other tissues.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Biological and medical sciences / Biological Clocks - genetics / Biological Clocks - physiology / Biological Clocks - radiation effects / Biomedical research / Bone marrow / Bone Marrow - innervation / Bone Marrow - metabolism / Bone Marrow - radiation effects / Bone Marrow Cells - metabolism / Bone Marrow Cells - radiation effects / Cell Line / Chemokine CXCL12 - genetics / Chemokine CXCL12 - metabolism / Chronobiology / Circadian rhythm / Circadian Rhythm - physiology / Circadian Rhythm - radiation effects / Circadian rhythms / Cues / Fluctuations / Fundamental and applied biological sciences. Psychology / Gene Expression Regulation / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Humanities and Social Sciences / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Osteoblasts / Peripheral nervous system. Autonomic nervous system. Neuromuscular transmission. Ganglionic transmission. Electric organ / Photic Stimulation / Physiology / Receptors, Adrenergic, beta-3 - deficiency / Receptors, Adrenergic, beta-3 - genetics / Receptors, Adrenergic, beta-3 - metabolism / Rodents / Science / Science (multidisciplinary) / Sp1 Transcription Factor - metabolism / Stem cells / Stromal Cells - metabolism / Sympathetic Nervous System - metabolism / Sympathetic Nervous System - radiation effects / Vertebrates: anatomy and physiology, studies on body, several organs or systems / Vertebrates: nervous system and sense organs