Mobilization of CD34+ Haematopoietic Stem Cells is Associated with a Functional Inactivation of the Integrin Very Late Antigen 4

The beta1 integrin very late antigen 4 (VLA-4) plays a central role in mobilization and homing of CD34+ cells. In this study, we examined the activation state of VLA-4 on CD34+ cells from bone marrow (BM) and peripheral blood (PB) by flow cytometry using a vascular cell adhesion molecule I-immunoglobulin (VCAM-I/IgG) fusion protein as soluble ligand. In an intraindividual analysis, we found a significantly reduced affinity and avidity of the VLA-4 receptor on CD34+ cells from PB during granulocyte colony-stimulating factor (G-CSF)-enhanced marrow recovery in comparison with steady-state BM. Moreover, the amount of circulating CD34+ cells during marrow recovery was inversely related to the activation state but not to the expression level of VLA-4, suggesting that a modulation of the functional state of VLA-4 is involved in the mobilization of CD34+ cells. Moreover, VLA-4 function on CD34+ cells from BM was associated with the maturation state of CD34+ cells as high-affinity VLA-4 receptors were observed on the vast majority of more primitive CD34+ cells. In addition, we found that Mg2+ ions as well as co-incubation of CD34+ cells with endothelial cells resulted in an activation of the VLA-4 receptor. In conclusion, modulation of the functional state of VLA-4 appears to be of relevance for the mobilization and homing of CD34+ haematopoietic stem cells.