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

H. Shen, T. Cheng, I. Olszak, E. Garcia-Zepeda, Z. Lu, S. Herrmann, R. Fallon, A. D. Luster, D. T. Scadden

Research output: Contribution to journalArticle

127 Scopus citations

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-1low, 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.

Original languageEnglish (US)
Pages (from-to)5027-5033
Number of pages7
JournalJournal of Immunology
Volume166
Issue number8
DOIs
StatePublished - Apr 15 2001

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Shen, H., Cheng, T., Olszak, I., Garcia-Zepeda, E., Lu, Z., Herrmann, S., Fallon, R., Luster, A. D., & Scadden, D. T. (2001). CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells. Journal of Immunology, 166(8), 5027-5033. https://doi.org/10.4049/jimmunol.166.8.5027