Here’s a summary by Jen Middleton of an article just out in Nature. We’ll have it as an archived research highlight soon.
Blood stem cells move between circulating blood and bone marrow, but little is known about what controls the traffic between the two. Reporting in Nature, Paul Frenette and colleagues from the Mount Sinai School of Medicine in New York show that levels of circulating HSCs fluctuate with natural circadian rhythms.
The team originally set out to study how a common treatment administered to patients before bone marrow transplants stimulates haematopoietic stem cells (HSCs). Working in mice, they noted by chance that HSC traffic increased under continuous exposure to light.
Under standard conditions of 12 hours light – 12 hours dark, the number of circulating HSCs in mice fluctuated predictably. Yet keeping mice in continuous light, disrupted this fluctuation pattern. Similar irregularities were observed in ‘jet-lagged’ mice. The team then looked at expression of a blood-signalling molecule called CXCL12 known to regulate HSC migration in the bone marrow. Levels of this chemokine fluctuated with exactly opposite timing such that when levels dropped, HSCs were released. This rhythmic pattern of CXCL12 expression was also disrupted in animals kept in constant light.
The “flight or fight” response releases HSCs from bone marrow, and the researchers wondered whether the neurons controlling this might also influence the patterns. A series of experiments found that these neurons (the adrenergic neurons of the sympathetic nervous system) delivered signals to the bone marrow in a pattern correlated with circadian rhythms. These signals triggered HSCs to enter circulation. Disrupting a particular kind of receptor known as the 3-adrenergic receptor was sufficient to disrupt the HSC cycle. Intriguingly, the bone-secreting cells or osteoblasts generally considered an important source of CXCL12 lack these receptors, so the neurons must directly target a different cell type.
These findings provide further clues to understanding the bone marrow stem cell niche. In practical terms, it may mean that more HSCs can be harvested from the bone marrow, by collecting at the right time of day.
Mendez-Ferrer S et al. (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature doi:10.1038/nature06685 Advance online publication 6 February 2008