Mechanism Of Stem Cell Mobilization

Despite the success of PBSCT, the exact mechanism involved in PBSC mobilization and homing is not well understood. There is evidence that cytotoxic agents disrupt normal marrow endothelial cell barriers and thus facilitate homing and release of hematopoietic stem cells (HSC). A number of different cytokines are also known to up- or downregulate specific adhesion molecules on both progenitor cells and endothelium and may mediate both the binding and release of HSC and progenitor cells.

A significant number of studies in the past few years have revealed insights into regulation of HSC release, migration, and homing as well as the mechanism of different mobilization pathways. Under steady-state conditions, most of the stem cells are maintained in the G0 phase of the cell cycle by interaction with stromal cells in the BM, while there is only a small proportion of stem cells in the S or G2/M phase of the cell cycle. Adhesive interaction between the CD34+ hematopoietic stem cell with cellular and matrix components of the BM environment are involved in stem cell mobilization.9 Primitive HSC express a wide range of cell adhesion molecules (CAM), including members of the integrin, selectin, immunoglobulin superfamily, and CD 44 families of adhesion molecules. The mobilization process is initiated by stress-induced activation of neutrophils and osteoclasts by chemotherapy and repeated stimulation with cytokines, resulting in shedding and release of membrane-bound stem cell factor (SCF), proliferation of progenitor cells, as well as activation and/or degradation of adhesion molecules such as very late antigen (VLA-4) and L-selectin. Recent studies suggest the interaction between CXCR4 and its ligand stromal-derived factor-1 (SDF-1) plays a key role in stem cell mobilization.10 Active signaling through SDF-1/CXCR4 and upregula-tion of adhesion molecules are required for homing, whereas downregulation of adhesion molecules and

Figure 94.1 A model for stem cell mobilization by G-CSF. In steady state (upper panel), stem cells are localized in close proximity to stromal cells. Retention is mediated by adhesion molecules such as VCAM-1/VLA-4 and through SDF-1/CXCR4 interactions. During mobilization (lower panel), G-CSF induces both cell proliferation and release of neutrophil proteases (elas-tase, cathepsin G, and MMPs), which participate in cell egress by degrading retention signals (VCAM-1 and SDF-1) and by remodeling the extracellular matrix. Upregulation of CXCR-4 on BM cells during G-CSF-induced mobilization suggests active participation of SDF-1/CXCR4 interactions in the migration of cells toward the blood. (From Lapidot and Petit10, used with Permission.)

disruption of SDF-1/CXCR4 signaling are required for mobilization of HSC. Lapidot and Petit have recently suggested a model wherein granulocyte colony-stimulating factor (G-CSF) stimulation induces proteases such as neutrophil elastase and other matrix metalloproteases that markedly reduce local BM of SDF-1, resulting in the egress of HSC and progenitor cells from BM into PB.10 Mobilized CD34+ cells have lower levels of VLA-4, c-kit expression, and CXCR4 expression compared with steady-state BM and PB. The release of CD34+ cells from the marrow is contingent upon an extensive decrease in L-selectin and moderate decrease in VLA-4 expression on CD34+ cells, and therefore, VLA-4 might have a role in facilitation of extravasation and release of CD34+ cells from the marrow into blood stream. The reduced c-kit expression before the egress of HSC in the circulation is inversely correlated with stem cell yield. The activation of the metalloproteinase (MMP)-9 leading to the release of c-kit-L is a decisive checkpoint for the mobilization of HSC as it promotes the recruitment of stem cells into PB. The proposed mechanism of stem cell mobilization is shown in Figure 94.1.

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