MOBILIZATION AND HOMING OF PERIPHERAL-BLOOD PROGENITORS IS RELATED TOREVERSIBLE DOWN-REGULATION OF ALPHA-4-BETA-1 INTEGRIN EXPRESSION AND FUNCTION

Despite the wide use of mobilized peripheral blood (PB) progenitor cel ls (PBPC) for clinical transplantation the mechanism(s) underlying the ir mobilization and subsequent engraftment are still unknown. We compa red the adhesive phenotype of CD34(+) colony-forming cells (CFC) in bo ne marrow (BM) and PB of normal donors before and after administration of granulocyte colony-stimulating factor (G-CSF) for 5 d. G-CSF-mobil ized PB CFC cells adhered significantly less to BM stroma, fibronectin , and to the alpha 4 beta 1 binding fibronectin peptide, CS1, because of decreased expression of the alpha 4 integrin. Since incubation of B MI CD34(+) cells for ii d with G-CSF at concentrations found in serum of G-CSF-treated individuals did not affect alpha 4-dependent adhesion , G-CSF may not be directly responsible for the decreased alpha 4-medi ated adhesion of PB CFC. Culture of G-CSF-mobilized PB CD34(+) cells w ith cytokines at concentrations found in BM stromal cultures upregulat ed alpha 4 expression and restored adhesion of mobilized PB CFC to str oma, fibronectin, and CSI. Adhesion of cultured, mobilized PB CFC to s troma and CSP could not be further upregulated by the beta 1 activatin g antibody, 8A2. This indicates acquisition of a maximally activated a lpha 4 beta 1 integrin once PB CFC have been removed from the in vivo mobilizing milieu. Thus, decreased alpha 4 expression on CD34(+) CFC i n PB may be responsible for the aberrant circulation of mobilized PB C D34(+) cells. Reex-pression of a maximally activated alpha 4 beta 1 in tegrin an mobilized PB CFC removed from the mobilizing in vivo milieu may contribute to the early engraftment of mobilized PBPC.