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

H Shen, T Cheng, I Olszak… - The Journal of …, 2001 - journals.aai.org
H Shen, T Cheng, I Olszak, E Garcia-Zepeda, Z Lu, S Herrmann, R Fallon, AD Luster…
The Journal of Immunology, 2001journals.aai.org
The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown
to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone
marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of
human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct
CXCR-4 expression or signaling profiles. CD34+ cells from BM were compared with blood:
either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher …
Abstract
The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct CXCR-4 expression or signaling profiles. CD34+ cells from BM were compared with blood: either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher levels of CXCR-4 surface expression on CD34+ cells from blood sources, mobilized peripheral blood, or cord blood were observed compared with BM (p= 0.0005 and p= 0.002, respectively). However, despite lower levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by either calcium flux or transmigration was proportionally greatest in cells derived from BM. Further, internalization of CXCR-4 in response to ligand, associated with receptor desensitization, was significantly lower on BM-derived cells. Therefore, preserved chemokine receptor signaling was highly associated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the methionine-SDF-1β analog that induces prolonged down-regulation/desensitization 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 dissociated in progenitor cells and that desensitization of CXCR-4 induces stem cell entry into the circulation.
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