Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells.

Mobilization of hematopoietic stem and progenitor cells from the bone marrow into the circulation by repetitive, daily stimulations with G-CSF alone, or in combination with cyclophosphamide, is increasingly used clinically; however, the mechanism is not fully understood. Moreover, following mobilization stem cells also home back to the bone marrow, suggesting that stem cell release/mobilization and homing are sequential events with physiological roles. Previously, a role for cytokines such as G-CSF and SCF, and adhesion molecules such as VLA-4 and P/E selectins, was determined for stem cell mobilization. Recent results using experimental animal models and samples from clinical mobilization protocols demonstrate major involvement of chemokines such as stromal derived factor-1 (SDF-1) and IL-8, as well as proteolytic enzymes such as elastase, cathepsin G, and various MMPs in the mobilization process. These results will be reviewed together with the central roles of SDF-1 and CXCR4 interactions in G-CSF or G-CSF in combination with cyclophosphamide-induced mobilization. Furthermore, the central role of this chemokine in stem cell homing to the bone marrow as well as retention of undifferentiated cells within this tissue will also be discussed.