Our bone marrow serves as the nursery for blood cells. All the circulating blood cells, red cells, white cells and platelets, are derived from a rare population of bone marrow cells known as hematopoietic stem cells or HSCs. Normally, the majority of HSCs rest and take a break while a small fraction of them proliferates and differentiates into progenitor cells that differentiate into mature red and white blood cells.
When the body needs more blood cells, for example after blood loss or during inflammation, more HSCs proliferate. However, what tells a HSC to cool it and take a powder or wake up get up and get dividing remains mysterious. Nevertheless, we do know one thing: location, location, location. Within the bone marrow are specialized site called “niches” that direct the behavior of the HSC. Quiescent niches, for example, house resting HSCs but other niches, known as vascular niches, are located in close proximity to the blood vessels that line the bone marrow sinusoids and harbor the minority of hard-working HSCs.
A new paper in Nature Medicine by Ingrid Winkler from the Mater Medical Research Institute and various other collaborators has clarified one of the mechanisms that tell HSCs to keep proliferating. A cell adhesion molecule called E-selectin is expressed by some bone marrow blood vessel cells (endothelial cells) in those blood vessels close to that thin layer of connective tissue that lines that the medullary cavity (endosteum).
E-selectin is normally expressed in endothelial cells that are experiencing inflammation. Inflammation is the result of tissue damage, and inflammation induces the synthesis E-selectin in endothelial cells. When white blood cells sense that damage has occurred that they are needed to fight off invading microorganisms, they bind to inflamed endothelial cells and crawl between them. Selectins, in general bind to sugar residues on the surfaces of cells, and are, therefore, members of a larger group of sugar-binding proteins known as lectins.
Back to the bone marrow: When mice that genetically lacked E-selectin were examined, they had fewer proliferating HSCs in their bone marrow. Was this due to problems with their HSCs? Clearly not, because when the HSCs from the E-selectin-deficient mice were transferred into normal mice, they divided perfectly well, and when normal HSCs were dropped into the bone marrow the E-selectin-deficient mice, they also failed to proliferate very much. The difference in these mice is their bone marrow microenvironments and not their stem cells.
HSCs divided less in E-selectin-deficient mice, but when normal mice were treated mice small molecules that inhibited E-selectin aged slower and also were protected against toxic stress-inducing conditions such as radiation and chemotherapeutic drugs. Inhibition of E-selectin inhibition improved mouse survival and recovery after radiation and chemotherapy.
As you might guess, E-selectin inhibitors are already in clinical trials for sickle-cell disease. This might very well accelerate the translation of these data such as these to the clinic. Just think, treating patients with E-selectin inhibitors before radiation or chemotherapy might protect the quiescent HSCs from the toxic effects of cancer therapeutics. Also, treatment that induces HSC quiescence also reduces leukocyte production, and could also elicit anti-inflammatory effects by reducing the systemic supply of leukocytes. These data from Winkler’s paper might be the impetus for designing ways to protect patients from the side effects of cancer therapy.
See 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).