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, Robert Fallon, A. D. Luster, D. T. Scadden

Research output: Contribution to journalArticle

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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
StatePublished - Apr 15 2001
Externally publishedYes

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Stem Cells
Bone Marrow Cells
Bone Marrow
Fetal Blood
CXCR Receptors
Fetal Stem Cells
Chemokine Receptors
Chemokines
Methionine
Blood Cells
Down-Regulation
Ligands
Calcium
Liver

ASJC Scopus subject areas

  • Immunology

Cite this

Shen, H., Cheng, T., Olszak, I., Garcia-Zepeda, E., Lu, Z., Herrmann, S., ... Scadden, D. T. (2001). CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells. Journal of Immunology, 166(8), 5027-5033.

CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells. / Shen, H.; Cheng, T.; Olszak, I.; Garcia-Zepeda, E.; Lu, Z.; Herrmann, S.; Fallon, Robert; Luster, A. D.; Scadden, D. T.

In: Journal of Immunology, Vol. 166, No. 8, 15.04.2001, p. 5027-5033.

Research output: Contribution to journalArticle

Shen, H, Cheng, T, Olszak, I, Garcia-Zepeda, E, Lu, Z, Herrmann, S, Fallon, R, Luster, AD & Scadden, DT 2001, 'CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells', Journal of Immunology, vol. 166, no. 8, pp. 5027-5033.
Shen H, Cheng T, Olszak I, Garcia-Zepeda E, Lu Z, Herrmann S et al. CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells. Journal of Immunology. 2001 Apr 15;166(8):5027-5033.
Shen, H. ; Cheng, T. ; Olszak, I. ; Garcia-Zepeda, E. ; Lu, Z. ; Herrmann, S. ; Fallon, Robert ; Luster, A. D. ; Scadden, D. T. / CXCR-4 Desensitization is associated with tissue localization of hemopoietic progenitor cells. In: Journal of Immunology. 2001 ; Vol. 166, No. 8. pp. 5027-5033.
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AU - Herrmann, S.

AU - Fallon, Robert

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