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*
AIDS Research Center, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129;
Genetics Institute, Cambridge, MA 02140; and
St. Louis University, St. Louis, MO 63103
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-1
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.
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