Stroma-derived factor 1 alpha induces a selective inhibition of human erythroid development via the functional upregulation of Fas/CD95 ligand

CXC chemokine receptor 4 (CXCR4), the high-affinity receptor for stroma-der ived factor 1 alpha (SDF-1 alpha), shows distinct patterns of expression in human CD34(+) haematopoietic progenitor cells induced to differentiate in vitro along the granulocytic and erythroid lineages. In serum-free liquid c ultures supplemented with stem cell factor (SCF), interleukin 3 (IL-3) and granulocyte colony-stimulating factor, the expression of surface CXCR4 prog ressively increased in cells differentiating along the granulocytic lineage . The addition in culture of 200 ng/ml of SDF-1 alpha, a concentration whic h maximally activated intracellular Ca2+ flux, only modestly affected the e xpression levels of CD15 and CD11b granulocytic antigens, as well as the to tal number of viable cells. On the other hand, in liquid cultures supplemen ted with SCF, IL-3 and erythropoietin, SDF-1 alpha induced the downregulati on of glycophorin A erythroid antigen, accompanied by a progressive decline in the number of viable erythroblasts. Moreover, in semisolid assays, SDF- 1 alpha significantly reduced the number of plurifocal erythroid colonies ( erythroid blast-forming units; BFU-E), whereas it did not affect granulocyt e-macrophage colony-forming units (CFU-GM). We also demonstrated that the i nhibitory effect of SDF-1 alpha on glycophorin A(+) erythroid cell developm ent was mediated by the functional upregulation of CD95L in erythroid cultu res. These data indicate that SDF-1 alpha plays a role as a negative regula tor of erythropoiesis.