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 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-1beta 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.
Shen
H
H
AIDS Research Center, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Cheng
T
T
Olszak
I
I
Garcia-Zepeda
E
E
Lu
Z
Z
Herrmann
S
S
Fallon
R
R
Luster
A D
AD
Scadden
D T
DT
D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000008:administration & dosage; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D009928:Organ Specificity / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D008024:Ligands; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; D002118:Calcium