Discovery of the Mechanism by which Stem Cells are Released from Bone Marrow has Vast Implications in Health and Disease

Nature, February 6, 2008

Researchers at Mt. Sinai Hospital in New York have identified the mechanisms that regulate the release of stem cells from bone marrow into the blood. It has long been known that bone marrow-derived stem cells regularly circulate throughout the blood, and many bone marrow transplantation procedures involve the harvesting of stem cells from the peripheral blood. Previously, however, the precise mechanisms by which the stem cells were released into the blood remained unknown. Dr. Paul Frenette and colleagues at the Mt. Sinai School of Medicine have now discovered that molecular adrenergic signals originating in the brain are sent via the sympathetic nervous system directly to "niches" within the bone marrow in which the stem cells reside, thereby triggering the release of the stem cells from these niches into the circulating blood.

The sympathetic nervous system is that part of the autonomic nervous system most commonly identified with the "fight or flight" response, but it is also highly sensitive to stress and is therefore easily activated by changes in circadian rhythms. All species exhibit circadian rhythms that are regulated by a biological "master clock" which in humans is anatomically located in the suprachiasmatic nucleus within the hypothalamus. External cues reset the biological clock daily, the most important one of which is light which stimulates highly photosensitive proteins in the photoreceptors of the retina of the eye from which signals are then transmitted across the retinohypothalamic tract to the suprachiasmatic nucleus which reinterprets the signals and retransmits them to the pineal gland where the hormone melatonin is secreted, and which is known to peak at night. From the hypothalamus through sympathetic nervous system pathways throughout the body, all physiological processes are regulated including cellular metabolism, hormone production, brain wave activity, body temperature, reproduction, and patterns of sleeping and eating, all of which are naturally entrained to the 24-hour cycle of the earth's rotation.

In this particular study, the Mt. Sinai researchers used a mouse model in which the maximum release of stem cells from the bone marrow into the circulating blood was observed to occur during periods of rest, although changes in light and experimentally induced "jet lag" in the mice were found to alter the patterns of stem cell release. These results are the first to indicate a circadian regulatory relationship between the cyclical "biological clock" and naturally produced endogenous stem cells. The discovery holds many implications for the important role of these rhythmic oscillations in regenerative medicine and also in the natural regeneration that continually occurs in healthy individuals on a daily basis. In patients who need stem cell transplantation, for example, the collection of their own stem cells may be optimized by timing the harvesting of the cells to coincide with those peak hours of release. Additionally, the discovery also highlights the importance of maintaining regular sleeping habits, especially in today's modern society, since the normal release of stem cells from the bone marrow into the circulating blood may be hindered by such factors as jet lag, sleep deprivation and other disruptions in natural circadian rhythms. The results of this study may offer one of the first concrete scientific explanations for the previously suspected correlation between night shift work and cancer, a causality which has been established by a number of previous studies and formally identified by the World Health Organization as well as by the International Agency for Research on Cancer, which in 2007 listed night shift work as "probably carcinogenic to humans." A disruption in natural sleeping rhythms which in turn disrupt the peak release times of stem cells from bone marrow into the circulating blood could interfere with the body's natural ability to repair itself daily and could therefore possibly also contribute to the formation of various types of cancer.