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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
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of adhesive interactions of progenitor cells with BM stromal
cells or extracellular matrix have been hypothesized to play a role in
stem cell trafficking. However, perhaps the most compelling model for
disruption of the normal processes governing stem cell localization is
that of mice engineered to be deficient in the chemokine receptor
CXCR-4 or its ligand, stroma-derived factor (SDF)-1. These animals have
normal fetal liver hemopoiesis, but fail to undergo the normal
translocation of cells to the BM microenvironment (1, 2, 3).
BM histology reveals normal blood cells, but no evidence of
hemopoietic activity. These data demonstrate the critical role for
CXCR-4 and SDF-1 in the developmental process of stem cell BM
homing. Data from other studies have indicated the presence of
CXCR-4 on progenitor cells from adult mice or humans and migration of
myeloid colony-forming cells toward a SDF-1 stimulus
(4, 5, 6, 7, 8, 9, 10). No difference was seen in the functional activity
of progenitor cells migrating to SDF-1 vs those that did not. In other
studies, CXCR-4-deficient progenitor cells transplanted into wild-type
mice have high circulating levels of myeloid and B lymphoid precursor
cells (11), indicating poor retention in the marrow
cavity. Conversely, cells which express high levels of CXCR-4 have
increased efficiency of hemopoietic engraftment on transplantation
(12). However, recent data regarding pertussis toxin
inhibition of G
i-linked signaling, which would
include CXCR-4 as well as other G protein-coupled receptors, did not
perturb BM engraftment (13). Rather, splenic engraftment
was diminished, raising the question of the specificity for BM
localization of CXCR-4 activation. Therefore, the participation of
CXCR-4 in the homeostasis of human stem cell populations remains
ill-defined. The presence of stem cell populations in either liquid
(umbilical cord blood (CB) and mobilized peripheral blood (mPB)) or
semisolid (BM) phase tissues provides an opportunity to assess the
physiology of CXCR-4 signaling in cell types of comparable hemologic
function but distinct anatomic location. We tested the hypothesis that
stem cell populations in the human demonstrate unique CXCR-4 expression
or signaling profiles dependent on the tissue of origin. In addition,
we sought to define the causal link between CXCR-4 signaling and tissue
localization through manipulation of CXCR-4 in vivo with a mouse
model.
We assessed preparations of cells typically used in transplantation, comparing BM with blood phase cells obtained from leukophereses after G-CSF mobilization (mPB) or CB from newborns. Profiles of surface expression, intracellular calcium flux, chemotaxis, and receptor internalization in response to ligand were analyzed and characteristics distinctive for cells resident in BM were defined. Manipulation of CXCR-4 signaling by induced desensitization to ligand by using a modified SDF-1 resulted in translocation of stem cells from BM to blood in the mouse. Therefore, we conclude that CXCR-4 signaling is a critical determinant of tissue localization of hemopoietic stem cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BM aspirates were collected from normal adult volunteers according to guidelines established by the Human Investigation Committee of the Massachusetts General Hospital (Boston, MA). Cord blood was obtained from the St. Louis University (St. Louis, MO) cord blood bank according to Institutional Review Board guidelines. CD34+ cells were purified by magnetic bead immunoselection (Miltenyi Biotec, Auburn, CA) from low-density cells obtained by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density centrifugation. The mean purity of CD34+ cells purified by this method was 94.6% as assessed by flow cytometry. CD34+ cells from G-CSF mPB of normal donors were collected by Isolex (Baxter Healthcare, Irvine, CA) cell processor (generous gift of Dr. Paul Prince, Baxter Healthcare). The purity of mPB CD34+ cells was 98% by flow cytometry.
Phenotypic analysis
Purified CD34+ cells were suspended in PBS containing 0.2% BSA and incubated with PE-conjugated anti-CXCR-4 or anti-CCR-5 (BD PharMingen, San Diego, CA), APC-conjugated anti-CD38, and PerCP-conjugated anti-CD34 (Becton Dickinson, Mountain View, CA) for 15 min at 4°C. After washing, cells were suspended in PBS or 1–2% paraformaldehyde PBS. In the case of CCR-3 and some experiments for CCR-5, labeling was conducted with mouse anti-human mAbs (LeukoSite, Cambridge, MA), followed by FITC or PE-conjugated affinity purified F(ab')2 goat anti-mouse IgG human absorbs (Tago, Burlingame, CA or Caltag, San Francisco, CA). Samples were analyzed by flow cytometry (FACSCalibur; Becton Dickinson) analyzing those populations positive for anti-CD34 staining.
Calcium flux
Calcium flux was performed as described previously (4, 14). Briefly, purified CD34+ cells were
loaded with Indo-1/AM (Molecular Probes, Eugene, OR) before staining
with FITC-conjugated anti-CD34. NIH 3T3 cells were used as negative
controls. Cells then were collected by flow cytometry (Coulter,
Hialeah, FL or FACSVantage; Becton Dickinson) for 
30 s before
stimulation to have baseline values for Indo-1 emission. Recombinant
human SDF-1 (PeproTech, Rocky Hill, NJ), was added at 1 µg/ml, and
data collection was continued for up to 3–5 min after the ligand
stimulation.
Chemotaxis assay
Cells (50,000) in 50 µl of HBSS buffer (Media Tech, Washington, DC) supplemented with 0.05% low endotoxin BSA (Sigma, St. Louis MO), were placed in the top wells of 48-well microchemotaxis chambers (Neuroprobe, Cabin John, MD; Refs. 15, 16, 17). A standard 5-µm pore polycarbonate filter (Poretics, Livermore, CA) was used to separate the cells from buffer alone (30 µl) or buffer containing recombinant chemokines. Cells were incubated at 37°C for 2 h and the cells that migrated across the filter and adhered to the bottom side were stained with Diff-Quick solution (Baxter Scientific, McGaw Park, IL). Chemotaxing cells were enumerated as cell number per x400 field under light microscopy.
CXCR-4 down-regulation by SDF-1
CD34+ cells were incubated with SDF-1
at 0, 10, 100, 1000, or 2000 ng/ml for 5, 10, 20, or 30 min or 1 h
at 37°C. After washing, cells were stained with PE-conjugated
anti-CXCR-4 and FITC-conjugated anti-CD34 as described above.
The reduction of median fluorescence intensity (MFI) for CXCR-4 after
stimulation with SDF-1 was calculated based on nonstimulated
controls.
Methionine (met)-SDF-1 in vivo administration and stem cell
quantitation
SJL mice aged 8–10 wk (The Jackson Laboratory, Bar Harbor, ME)
were injected retroorbitally with 300 µg of met-SDF (Provided by
Genetics Institute, Cambridge, MA) in PBS i.v. Control mice were
injected with either unmodified native SDF-1 (PeproTech) or PBS
only. Mouse blood was collected before injection and at 24 and 48
h after injection. A total of 100 µl of blood was mixed with an Ab
cocktail including biotinylated lineage markers (CD3, CD4, CD8, B220,
Gr-1, Mac-1 (Caltac), and TER-119 (BD PharMingen, San Diego, CA)) and
fluorochrome-labeled stem cell markers (Thy-1-APC, Sca-1-PE, and
c-kit-Tri (Caltac)), and incubated at 4°C for 15 min. Cells were
washed with PBS, incubated with steptavidin-FITC at 4°C for 15 min,
and treated with RBC lysing solution (Becton Dickinson) at room
temperature for 10 min. The final cell suspension was fixed with 2%
paraformaldehyde before flow cytometric analysis with a FACSCalibur
instrument.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fig. 1). Differences were noted in the BM
CD34+ cells compared with either of the
liquid-phase cell sources. Specifically, CXCR-4 was noted in a
significantly smaller fraction of BM-derived cells (39.9 ± 4.4%)
compared with CB (66.5 ± 6.3) or mPB (69.4 ± 4.5%;
p = 0.002 and p = 0.0005,
respectively). In addition, CC chemokine receptors CCR-5 and CCR-3 were
detectable only in cells derived from BM. The proportion of cells
staining with these Abs was small, 11.99 ± 6.26% for CCR-5 and
3.02 ± 0.69% for CCR-3, but quantifiable compared with the
negative staining consistently noted on the CB or mPB. Whether
detectable receptor levels varied based on the level of differentiation
of the cells was assessed by using populations distinguished by the
presence or absence of the differentiation marker, CD38. Neither CXCR-4
nor CCR-3 expression was dependent on differentiation state. However,
the level of CCR-5 on the
CD34+CD38- subpopulation
was marginally detectable, a phenomenon we had reported previously and
confirmed by RT PCR and response to ligand (4). MFI
between the tissues for CXCR-4 staining was substantially different (BM
vs CB, p = 0.03; BM vs mPB, p = 0.05),
suggesting that receptor density was also dependent on tissue source
and was lowest in BM. However, an alteration in Ab binding attributable
to differences in receptor configuration cannot be excluded based on
these data.
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B). SDF-1 dose titration did not reveal
differences in the ED50 between the
CXCR-4+CD34+ cells from the
different tissue sources.
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). The response was
concentration-dependent and was greatest at 100 ng/ml for all sources
of CD34+ cells, as has been noted in other
studies with multiple cell types (5, 6, 9, 10). Therefore,
it is unlikely that variable ligand/receptor interactions potentially
affecting the ED50 could account for the
differences between the populations ofCD34+
cells.
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demonstrates the rapid down-regulation
of CXCR-4 and the extent of down-regulation based on the tissue of
origin of the CD34+ cells. The rate of change in
CXCR-4 expression was consistent among the various populations (data
not shown), but the proportion of cells decreasing their surface
expression was dependent on the cell source. BM
CD34+ cells maintained surface expression on a
larger fraction of cells compared with CB or mPB
CD34+ cells (Fig. 3, C and
D). There were statistically significant differences
(p < 0.05) between either CB or mPB and BM,
though not between CB and mPB (Fig. 3C). The down-modulation
of CXCR-4 inversely correlated with responsiveness of cells to ligand
as measured by calcium flux or transmigration.
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(met-SDF-1) PBS or native, unmodified SDF-1. The
met-SDF-1 compound interacts with CXCR-4 with similar kinetics to
unmodified ligand but induces marked alteration in the recycling time
of the receptor, delaying its reappearance on the cell surface to 48
h in mouse hemopoietic progenitor cells (18). It induces
receptor down-modulation and thereby desensitization over that seen
with native protein. Intravenous injection of mice with met-SDF-1
(300 µg per mouse in PBS) induced a marked increase in the
circulating numbers of primitive hemopoietic progenitor cells as
assessed by the immunophenotype of Lin-,
Thy-1low, Sca-1+, and
c-kit+ (Refs. 19, 20 ; Fig. 4). A 32.5- and 43.8-fold increase in
stem cells was observed in the PBMC from the met-SDF-1-treated mice
at 24 and 48 h, respectively. In contrast, a 0.91- and 1.86-fold
increase was noted in the mononuclear cell fraction of the blood from
control animals injected with same volume of PBS. Native SDF-1 at a
comparable dose did not result in mobilization of primitive cells
significantly above that of PBS control. Progenitor populations
(Lin-, Thy-1low,
Sca-1-, and c-kit+) were
not significantly different between the pretreatment and treatment
groups for either PBS or met-SDF-1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-arrestins, modulate downstream effects of receptor/ligand
interaction (21, 22, 23, 24). After internalization of receptor by
endocytosis, uncoupling from G proteins persists even after cell
surface reexpression (22, 23, 24), resulting in ligand
interaction without induction of a functional effect such as calcium
flux or cell migration. Uncoupling of receptor expression and signaling
has been noted for CXCR-4 in differentiating B cells without clear
mechanism (25), and we investigated whether similar
phenomena could account for the variable localization of primitive
hemopoietic cells which express the known stem cell homing determinant,
CXCR-4. We characterized the expression levels, rates of internalization, and functional outcomes of receptor-ligand pairing of human CD34+ cells and noted clear dissociation of expression and function of CXCR-4. A similar distinction between receptor expression and function was noted previously by us in the context of the chemokine receptor serving as a HIV coreceptor; the presence of the receptor was not uniformly predictive of susceptibility to HIV-1 infection (4). In the context of the present study, the relationship of receptor expression to cellular calcium flux or transmigration was distinct for populations of CD34+ cells in the circulation (CB and mPB) vs in the BM space.
The level of cell surface CXCR-4 was lowest in BM-derived cells. However, the data do not permit evaluation of whether the lower level of CXCR-4 actually represents alteration in the partitioning of internal vs cell surface receptors or an overall decline in total receptor number per cell. The lower surface expression of CXCR-4 on BM-derived cells could be attributable to high levels of SDF-1 in the BM microenvironment. However, lower CXCR-4 on BM CD34+ cells was not associated with uncoupling. Rather, these cells demonstrated the highest fractional response to SDF-1 as measured by the functional assays of calcium flux and cell transmigration. Although down-modulation of the receptors was noted to be of similar rate regardless of the cell source, the extent of down-modulation was highly cell-source specific. Cells derived from CB or mPB down-modulated to a greater extent than did BM CD34+ cells. Interestingly, the decreased down modulation observed in BM CD34+ cells corresponded to a more sustained calcium flux in the presence of ligand. The relationship of these two phenomenon is not well defined, but sustained increases in intracellular calcium have also been observed in pre-B cells after SDF-1 stimulation (25). The down-modulation of receptor may reflect either clathrin-coated, pit-mediated endocytosis or reexpression rates and depend on multiple aspects of the sequestration pathway (26). The level at which this pathway is altered in cells of BM vs blood is unclear, but CD34+ cells segregate in their kinetics of receptor cell surface expression after interaction with ligand according to their tissue of origin. Therefore, the modulation of CXCR-4 signaling and recycling was highly associated with the location of the cells to either BM or blood, but the causal relationship between CXCR-4 signaling and location could not be determined from this type of analysis.
To directly assess whether receptor expression could dictate the basis
for cell localization, we pharmacologically manipulated CXCR-4 surface
expression in the mouse. SDF-1 in which a N-terminal methionine has
been added (met-SDF-1) binds to CXCR-4 with slightly lower affinity
than the unmodified SDF-1 (18). However, the
interaction of met-SDF-1 with CXCR-4 leads to a more prolonged
down-regulation of CXCR-4 on the cell surface (18). After
exposure of cells to saturating concentrations of met-SDF-1 or
SDF-1, cell surface expression of CXCR-4 decreases. Whereas CXCR-4
reexpression is observed after the wash-out of SDF-1, marked
reduction of surface CXCR-4 continues to be present for 72 after
removing met-SDF-1 from the culture (18). Though these
results were defined in human cells and cannot be readily tested in
mouse cells because of the lack of Ab reagents, we conjectured that a
similar response was likely. Therefore, we used met-SDF-1 as a
method of achieving desensitization through sustained down-regulation
of CXCR-4 and examined the effects on circulating levels of stem cells.
The abundance of cells with a stem cell phenotype
(Lin-, Sca-1+,
Thy-1low, and c-kit+) rose
dramatically in the peripheral blood of mice and persisted for at least
48 h after exposure. A similar phenomenon was not observed with
the use of native SDF-1, suggesting that the down-regulation of
receptor is critical for the mobilization effect. The relationship of
receptor down-modulation observed in the circulating progenitors of
human peripheral blood and CB is mimicked by met-SDF-1 and shown to
result in the mobilization phenomenon. To the extent that
down-modulation and desensitization can be equated, met-SDF-1
stimulation demonstrates the functional relationship of altered CXCR-4
signaling to cell localization. Therefore, the distinct CXCR-4 response
profiles between the BM vs blood phases of stem cell pools may be
causative of cell circulation rather than simply associated. We
speculate that the manipulation of CXCR-4 may be a critical focal point
for altering the BM or blood tropism of stem cells and will have
therapeutic implications for cell harvesting and engraftment.
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Acknowledgments |
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Footnotes |
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2 Current address: Instituto de Investigaciones Biomédicas, UNAM, CU 04510, México, D.F. México.
3 Current address: Indiana University Cancer Research Institute, Indianapolis, IN 46202.
4 Address correspondence and reprint requests to Dr. David T. Scadden, Massachusetts General Hospital, 149 13th Street, Room 5212, Boston, MA 02129.
5 Abbreviations used in this paper: BM, bone marrow; SDF, stroma-derived factor; CB, umbilical cord blood; mPB, mobilized peripheral blood; MFI, median fluorescence intensity; met, methionine.
Received for publication May 12, 2000. Accepted for publication February 13, 2001.
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References |
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correlates with down-modulation of CXCR4. J. Virol. 73:4582. stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induced migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood 95:2505.-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 271:363.[Abstract]
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T. Papayannopoulou Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization Blood, March 1, 2004; 103(5): 1580 - 1585. [Abstract] [Full Text] [PDF]
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L. M. Pelus, H. Bian, A. G. King, and S. Fukuda Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRO{beta}/CXCL2 and GRO{beta}T /CXCL2{Delta}4 Blood, January 1, 2004; 103(1): 110 - 119. [Abstract] [Full Text] [PDF]
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 N. Rosenthal Prometheus's Vulture and the Stem-Cell Promise N. Engl. J. Med., July 17, 2003; 349(3): 267 - 274. [Full Text] [PDF]
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T. Papayannopoulou, G. V. Priestley, H. Bonig, and B. Nakamoto The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization Blood, June 15, 2003; 101(12): 4739 - 4747. [Abstract] [Full Text] [PDF]
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K. Balabanian, J. Couderc, L. Bouchet-Delbos, A. Amara, D. Berrebi, A. Foussat, F. Baleux, A. Portier, I. Durand-Gasselin, R. L. Coffman, et al. Role of the Chemokine Stromal Cell-Derived Factor 1 in Autoantibody Production and Nephritis in Murine Lupus J. Immunol., March 15, 2003; 170(6): 3392 - 3400. [Abstract] [Full Text] [PDF]
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O. Kollet, I. Petit, J. Kahn, S. Samira, A. Dar, A. Peled, V. Deutsch, M. Gunetti, W. Piacibello, A. Nagler, et al. Human CD34+CXCR4- sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation Blood, September 26, 2002; 100(8): 2778 - 2786. [Abstract] [Full Text] [PDF]
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A. E. Hauser, G. F. Debes, S. Arce, G. Cassese, A. Hamann, A. Radbruch, and R. A. Manz Chemotactic Responsiveness Toward Ligands for CXCR3 and CXCR4 Is Regulated on Plasma Blasts During the Time Course of a Memory Immune Response J. Immunol., August 1, 2002; 169(3): 1277 - 1282. [Abstract] [Full Text] [PDF]
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G. F. Debes, U. E. Hopken, and A. Hamann In Vivo Differentiated Cytokine-Producing CD4+ T Cells Express Functional CCR7 J. Immunol., June 1, 2002; 168(11): 5441 - 5447. [Abstract] [Full Text] [PDF]
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J. Cashman, I. Clark-Lewis, A. Eaves, and C. Eaves Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice Blood, February 1, 2002; 99(3): 792 - 799. [Abstract] [Full Text] [PDF]
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K. Balabanian, A. Foussat, L. Bouchet-Delbos, J. Couderc, R. Krzysiek, A. Amara, F. Baleux, A. Portier, P. Galanaud, and D. Emilie Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant Blood, January 15, 2002; 99(2): 427 - 436. [Abstract] [Full Text] [PDF]
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E. A. Sweeney, H. Lortat-Jacob, G. V. Priestley, B. Nakamoto, and T. Papayannopoulou Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells Blood, January 1, 2002; 99(1): 44 - 51. [Abstract] [Full Text] [PDF]
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 G. A. McQuibban, G. S. Butler, J.-H. Gong, L. Bendall, C. Power, I. Clark-Lewis, and C. M. Overall Matrix Metalloproteinase Activity Inactivates the CXC Chemokine Stromal Cell-derived Factor-1 J. Biol. Chem., November 16, 2001; 276(47): 43503 - 43508. [Abstract] [Full Text] [PDF]
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D. E. Wright, E. P. Bowman, A. J. Wagers, E. C. Butcher, and I. L. Weissman Hematopoietic Stem Cells Are Uniquely Selective in Their Migratory Response to Chemokines J. Exp. Med., May 6, 2002; 195(9): 1145 - 1154. [Abstract] [Full Text] [PDF]
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