Stem cells in bone marrow keep time with light. Credit: Getty/Jessica Kolman

Blood stem cells move between the circulating blood and the 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 the levels of circulating haematopoietic stem cells 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) to move into the bloodstream. Working in mice, they noted by chance that HSC traffic increased under continuous exposure to light.

Under standard conditions of 12 hours of light followed by 12 hours of dark, the number of circulating HSCs in mice fluctuated predictably; however, keeping mice in continuous light disrupted this fluctuation pattern. Similar irregularities were observed in 'jet-lagged' mice, when light-dark patterns were shifted by 12 hours. The team then looked at the expression of a blood signalling molecule called CXCL12, which is known to regulate HSC migration in the bone marrow. Levels of this chemokine fluctuated inversely with HSC migration such that when CXCL12 levels dropped, HSC release increased. This rhythmic pattern of CXCL12 expression was also disrupted in mice that were kept in constant light.

The 'flight-or-fight' response releases HSCs from the bone marrow, and the researchers wondered whether the neurons controlling this response might also influence the patterns of CXCL12 expression. Through a series of experiments, they found that these neurons (the adrenergic neurons of the sympathetic nervous system) delivered signals to the bone marrow in a pattern that correlated with circadian rhythms. These signals triggered HSCs to enter circulation. Disrupting a particular kind of receptor known as the b3-adrenergic receptor was sufficient to interfere with the HSC cycle. Intriguingly, the bone-secreting cells, or osteoblasts, which are 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 for 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 them at the right time of day.