Stem Cells

Clocking Out

Science Signaling  01 Apr 2008:
Vol. 1, Issue 13, pp. ec117
DOI: 10.1126/stke.113ec117

Under homeostatic conditions, hematopoietic stem cells (HSCs) circulate in the blood, albeit in low numbers. Retention of HSCs in the bone marrow (BM) is mediated by the chemokine CXCL12. Pharmacological agents that mobilize HSCs from the BM cause the degradation of CXCL12; however, the mechanism responsible for physiological egress of HSCs is unknown. When mice were housed under standard light-dark cycles, Méndez-Ferrer et al. noticed that the numbers of HSCs in the circulation peaked 5 hours after light was initiated and were at their lowest 5 hours after darkness began. Enzyme-linked immunosorbent assays and quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses revealed that the expression of Cxcl12 and the abundance of CXCL12 in the BM were lower when HSCs were most abundant in the circulation and higher when HSCs were retained in the BM. The regulation of circadian activity by the suprachiasmatic nucleus in the hypothalamus is mediated by the release of adrenergic neurotransmitters by the sympathetic nervous system (SNS). Pharmacological or surgical disruption of the SNS in mice abolished the circadian control of Cxcl12 expression and HSC circulation. Experiments with pharmacological agents showed that β3-adrenergic receptor (β3-AR) stimulation resulted in reduced Cxcl12 expression in the BM. Circadian variation of Cxcl12 expression and the number of circulating HSCs was disrupted in β3-AR-deficient mice. Finally, the abundance and nuclear localization of the transcription factor Sp1, which activates Cxcl12 expression, were lower in primary BM stromal cells treated with a β-AR agonist than in untreated cells. Together, these data provide a potential mechanism for the physiological circulation of stem cells and raise the question of why this process should be under circadian control (see commentary by Scadden).

S. Méndez-Ferrer, D. Lucas, M. Battista, P. S. Frenette, Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442-447 (2008). [PubMed]

D. T. Scadden, Stem cells traffic in time. Nature 452, 416-417 (2008). [PubMed]