Editors' ChoiceCancer

E-Selectin Gets HSCs Buzzing.

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Science Translational Medicine  07 Nov 2012:
Vol. 4, Issue 159, pp. 159ec202
DOI: 10.1126/scitranslmed.3005248

The bone marrow—the primary site of blood cell production—has a set hierarchy that can be compared with a beehive. Indeed, all circulating cells (the workers and the drones) are derived from a rare population called hematopoietic stem cells (HSCs), the queen bees. Indeed, under normal conditions most HSCs receive the royal treatment: resting while only a tiny fraction proliferates and differentiates into downstream progenitors. In times of higher demand—for instance, during inflammation or after blood loss—more HSCs proliferate. Yet, the mechanisms that determine which HSCs have to fulfill their proliferate duties are largely a mystery. What we do know is that as with all things, location is everything: There are niches specialized for resting HSCs, called quiescent niches, and others that harbor the minority of HSCs hard at work. These so-called vascular niches are located close to endothelial cells that line the bone marrow sinusoids.

Winkler et al. have now made a beeline toward the mechanism that keeps HSCs proliferating. They discovered a new function for the cell adhesion molecule E-selectin, which is expressed by some bone marrow endothelial cells in certain microdomains close to the endosteum. Mice that lacked E-selectin had fewer proliferating HSCs, and adoptive transfer experiments determined that this function is HSC extrinsic; it can be assigned to the bone marrow microenvironment rather than to the stem cells themselves. HSCs that cycled less in E-selectin-deficient mice or in mice treated with a small-molecule inhibitor for E-selectin aged slower and were protected against toxic stressors, including radiation and chemotherapeutic drugs. Indeed, E-selectin inhibition improved mouse survival and recovery after radio and chemotherapy.

E-selectin inhibitors are already in clinical trials for sickle cell disease, which may accelerate the translation of these data to the clinic. Treating patients with E-selectin inhibitors before radiation or chemotherapy may protect the quiescent cells from toxic side effects of cancer therapeutics. Moreover, treatment that induces HSC quiescence also reduces leukocyte production, and could therefore elicit anti-inflammatory effects by reducing the systemic supply of leukocytes. By exploring the hive mentality of the blood system and protecting the queens, Winkler et al. may have found a way to protect patients from the side effects of cancer therapy.

I. G. Winkler et al., Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med., published online 21 October 2012 (10.1038/nm.2969). [Abstract]

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