Mechanisms of HSC Mobilization

Although the migratory capacity of stem cells has long been realized in the setting of transplantation, and stem cells have been identified in the peripheral blood (Till and McCulloch 1961, Goodman and Hodgson 1962), it was not realized until the 1980s that high-dose chemotherapy could be used to mobilize clinically useful numbers of HSCs into the peripheral blood for transplantation (Juttner et al. 1985. Schwartzberg LS et al. 1992, Buckner 1999). Like homing and engraftment, mobilization involves interactions between the stem cell and the bone marrow niche as well as the vasculature. Mobilization is achieved in the clinical setting most often by administration of granulocyte-colony stimulating factor (G-CSF). This method has replaced primary bone marrow harvesting as the method of choice to obtain HSCs for transplantation (Fu and Liesveld 2000, Thomas et al. 2002).

While successful engraftment requires the establishment of strong connections between stem cells and the niche, degradation of portions of the niche is required for stem cell mobilization. For example, a marked increase in neutrophil elastase and cathepsin-G proteases that can degrade VCAM-1 is observed in the bone marrow following administration of G-CSF or cyclophosphamide (Levesque et al. 2002). Similarly, IL-8-induced mobilization is also associated with neutrophil-mediated increases in matrix metalloproteinase-9 (Pruijt et al. 2002).

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