CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells

The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stern cell s from the fetal liver to the bone marrow (BM). We hypothesized that if CXC R-4 plays a crucial role in the localization of human hemopoiesis, stem cel ls from distinct tissue sources should demonstrate distinct CXCR-4 expressi on or signaling profiles. CD34(+) cells from BM were compared with blood: e ither mobilized peripheral blood or umbilical cord blood. Unexpectedly, sig nificantly higher levels of CXCR-4 surface expression on CD34(+) cells from blood sources, mobilized peripheral blood, or cord blood were observed com pared with BM (p = 0.0005 and p = 0.002, respectively). However, despite lo wer levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by e ither calcium flux or transmigration was proportionally greatest in cells d erived from BM. Further, internalization of CXCR-4 in response to ligand, a ssociated with receptor desensitization, was significantly lower on BM-deri ved cells. Therefore, preserved chemokine receptor signaling was highly ass ociated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the niet hionine-SDF-1 beta analog that induces prolonged down-regulation/desensitiz ation of CXCR-4 and observed mobilization of Lin(-), Sca-1(+), Thy-1(low), and c-kit(+) hemopoietic progenitor cells to the peripheral blood with a > 30-fold increase compared with PBS control (p = 0.0007 day 1 and p = 0.004 day 2). These data demonstrate that CXCR-4 expression and function can be d issociated in progenitor cells and that desensitization of CXCR-4 induces s tem cell entry into the circulation. The Journal of Immunology.