Haematopoietic stem cell release is regulated by circadian oscillations

  title={Haematopoietic stem cell release is regulated by circadian oscillations},
  author={Sim{\'o}n M{\'e}ndez-Ferrer and Daniel Lucas and Michela Battista and Paul S. Frenette},
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… 
Circadian rhythms, adrenergic hormones and trafficking of hematopoietic stem cells
This review summarizes recent findings on the circadian regulation of HSC release in the bone marrow examining the molecular mechanisms through which the central molecular clock regulates CXCL12 in bone marrow stromal cells through rhythmic secretion of adrenergic hormones locally delivered in theBone marrow by nerve terminals from the SNS.
Circadian rhythms influence hematopoietic stem cells
HSC traffic and hematopoiesis do not escape the circadian regulation that controls most physiological processes and the timing of stem cell harvest or infusion may impact the yield or engraftment, respectively and may result in better therapeutic outcomes.
Stem cells: Harvest in the right season
  • F. Cesari
  • Biology
    Nature Reviews Molecular Cell Biology
  • 2008
The mobilization of HSCs follows a physiologically regulated circadian rhythm and core genes of the circadian clock, such as Bmal1, Per1 and Per2, orchestrate Cxcl12 expression and the trafficking of stem cells, probably by regulating the rhythmic secretion of noradrenaline from the nerve terminals.
Hematopoietic-Extrinsic Cues Dictate Circadian Redistribution of Mature and Immature Hematopoietic Cells in Blood and Spleen
Hmatopoietic-extrinsic cues are established as causal for circadian redistribution of circulating mature/immature blood cells and implicate cortisol as the conveyor of circadian input to bone marrow stroma and mediator of the circadian leukocyte oscillation.
Adrenergic Modulation of Hematopoiesis
The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of he matopoietic disorders and for HSC transplantation however the complexity of the system demands further studies.
Adrenergic nerves govern circadian leukocyte recruitment to tissues.
The Autonomic Nervous System Pulls the Strings to Coordinate Circadian HSC Functions
The critical role of different neurotransmitter receptors in the bone marrow microenvironment to channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands is highlighted.
Altered expression of circadian clock genes during peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor
Significant correlations between the levels of circadian clock gene mRNAs and the plasma level of noradrenaline, a sympathetic nervous system neurotransmitter, were established and may be novel therapeutic targets for increasing stem cell yields in PBSC donors.
Induction of Circadian Rhythm in Cultured Human Mesenchymal Stem Cells by Serum Shock and cAMP Analogs in Vitro
It is shown that repeated circadian oscillations could be induced in both cultured bone marrow‐derived mesenchymal‐ and adipose‐derived stem cells (MSCs and ASCs, respectively) by serum shock and the novel finding of rhythmic clock gene expression induced by cAMP analogs showed similarities as well as differences to serum‐induced oscillations.
Circadian Clock Genes Modulate Human Bone Marrow Mesenchymal Stem Cell Differentiation, Migration and Cell Cycle
Investigation of the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities, showed that CR plays a role in theregulation of h MSCs differentiation and division, and likely represent key factor in maintaining hMSCS properties.


Identification of the haematopoietic stem cell niche and control of the niche size
It is concluded that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of H SCs by regulating niche size.
Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide.
It is reported that mobilization of HPCs by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on H PCs resident in the BM and mobilized into the PB.
G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4
It is suggested that manipulation of SDF-1–CXCR4 interactions may be a means with which to control the navigation of progenitors between the BM and blood to improve the outcome of clinical stem cell transplantation.
G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow.
Data suggest a model in which G-CSF, through an indirect mechanism, potently inhibits osteoblast activity resulting in decreased CXCL12 expression in the bone marrow, which ultimately leads to HPC mobilization.
Circadian rhythms: mechanisms and therapeutic implications.
The rhythmic control of xenobiotic detoxification provides the molecular basis for the dosing time-dependence of drug toxicities and efficacy and can in turn be used in improving or designing chronotherapeutics for the patients who suffer from many of the major human diseases.
Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization.
A full understanding of the directional cues that control the migratory behavior and the fate of stem/progenitor cells once they migrate out of bone marrow will await further experimentation, aiming to bridge the current gaps in knowledge.