The ability of HSCs to mobilize and then return, or home, tothe niche relies on specific molecular recognition, cell-celladhesion/disengagement, transendothelial migration, and finallyanchoring to the BM niche (6, 51, 52, 73). The chemokine SDF-1and its receptor CXCR4 (51, 74, 75) as well as underlying signalingpathways, including the Rac family molecules, regulate HSC mobilizationand homing but also play a role in cell survival and proliferation(51, 76). Endothelial cells, osteoblasts, and other stromalcells constitutively express SDF-1, while HSCs express CXCR4(77, 78). SDF-1 generated from endothelial cells induces HSCsto undergo transendothelial migration mediated by E- and P-selectins(79). Activation of adhesion molecules such as VLA-4 and leukocytefunction antigen-1 (LFA-1) is also required for this processand the subsequent migration in BM toward the osteoblast surface(38). Likewise, high levels of SDF-1 on the surface of osteoblastsattract HSCs to return home to the osteoblast niche. The RhoGTPases Rac1 and Rac2, in response to SDF-1 signals, are alsoinvolved in regulating HSC mobilization and homing (80).
G-CSF induces HSC and progenitor cell mobilization and is widelyused clinically during stem cell–based transplantationprocedures. Recent studies revealed that the mechanism involvedis primarily a decrease of SDF-1 in osteoblasts, with an increaseof SDF-1 in peripheral circulation after G-CSF treatment (81).G-CSF also induces proteolytic enzymes such as elastase, cathepsinG, MMP-2, and MMP-9 (required for cells to penetrate the endothelium),which inactivates SDF-1 through cleavage of its NH2-terminalsignal sequence (82). In addition, G-CSF could regulate SDF-1expression in BM at the transcriptional level (83, 84). Duringstem cell homing HSCs expressing CXCR4 are attracted to theosteoblastic niche, which expresses high levels of SDF-1 (36,38), and the adherens complex formed by N-cadherin and ß-cateninmay play a crucial role for anchoring HSCs to the osteoblasticniche (6, 31).