|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 100-110
In Vitro Behavior of Hematopoietic Progenitor Cells Under the
Influence of Chemoattractants: Stromal Cell-Derived Factor-1,
Steel Factor, and the Bone Marrow Environment
By
Chang H. Kim and
Hal E. Broxmeyer
From the Departments of Microbiology/Immunology, Medicine and the
Walther Oncology Center, Indiana University School of Medicine,
Indianapolis; and the Walther Cancer Institute, Indianapolis, IN.
 |
ABSTRACT |
How multiple chemoattractants cooperate in directing the migration
of hematopoietic progenitor cells (HPC) for homing and peripheral blood
mobilization has not yet been established. We report here the behavior
of HPC under the influence of two different chemoattractants, stromal
cell-derived factor (SDF)-1 and steel factor (SLF), and the chemotactic
nature of the bone marrow (BM) environment using a two-chamber in vitro
migration system. Various formulae were adopted to quantitate these
effects. Based on these quantitations, SDF-1 showed only chemotactic
activity, while SLF showed both chemotactic and chemokinetic activities
on factor-dependent MO7e cells. SLF, like SDF-1, attracted human HPC
from a population of CD34+ cells and induced actin
polymerization in MO7e cells. SLF and SDF-1 cooperated in attracting
MO7e cells, as well as cord blood (CB) and BM CD34+
cells. A negative concentration gradient of SLF and SDF-1, formed by
the presence of chemoattractants in the upper chamber, showed potent
inhibitory effects on MO7e cell migration induced by either of these
chemoattractants in the lower chamber, and SDF-1 and SLF were
synergistic in mobilizing cells to the lower chamber from this negative
chemoattractant gradient. Plasma obtained from BM aspirates, but not CB
or peripheral blood, showed strong chemotactic effects on BM and CB
CD34+ cells, and an inhibitory effect in a negative
gradient on SDF-1-dependent CD34+ cell migration. These
in vitro migration experiments suggest that chemoattractants such as
SDF-1 and SLF with other unidentified BM chemoattractants may be
involved cooperatively in the migration of HPC to the BM and in
preventing spontaneous mobilization of HPC out of the BM.
| |
INTRODUCTION |
HEMATOPOIETIC progenitor cells (HPC) home
to the extravascular compartment of the bone marrow (BM) during
transplantation.1-5 Also, during fetal development, the
multipotential and self-renewing hematopoietic stem cells migrate to
the BM from the fetal liver. Chemoattractants may play a role in
directing migration of hematopoietic stem cells and HPC to the BM, but
this has not yet been clearly defined. In another direction, HPCs are
mobilized from the BM to the peripheral blood (PB) in response to
injected cytokines such as granulocyte-macrophage colony-stimulating
factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and
Steel factor (SLF).6-9 The mechanisms involved in this
mobilization of HPC from BM to PB are not known. It is possible that
chemoattractants may play a direct role in mobilization of HPC,
although other functions of cytokines such as proliferation, modulation
of adhesion molecules, or alteration of the blood-BM barrier, may be
important for these effects.4 For example, G-CSF and GM-CSF
appear to have no chemotactic or chemokinetic effects on HPC, while
SLF, interleukin (IL)-3, and IL-11 have been reported to chemoattract
murine HPC.10
Stromal cell-derived factor-1 (SDF-1), also called pre-B-cell
growth-stimulating factor (PBSF)11-14 has been reported to
be a powerful chemoattractant for lymphocytes, monocytes, and primary
CD34+ cells.15,16 Mice lacking SDF-1 died
perinataly and had reduced numbers of B-cell progenitors in fetal liver
and BM.17 These mutant mice also showed reduced numbers of
myeloid progenitor cells in BM, but normal numbers in fetal liver.
These results suggested that SDF-1 might be involved in the migration
of hematopoietic stem cells from fetal liver to BM during fetal
development. SDF-1 is a ligand for the LESTR/fusin/CXCR4 receptor and
prevents T-cell line-adapted human immunodeficiency virus (HIV)-1
infection.18-22 SDF-1 mobilizes calcium and reorganizes
actin structure in CXCR4-transfected Chinese hamster ovary
cells.15,16
Two types of chemoattraction are distinguishable on the basis of
direction of cell attraction in various chemoattractant gradients.
Chemotaxis is the attraction of cells only in a positive gradient,
while chemokinesis reflects activation of cell motility and an
induction of cell migration in a random direction by a chemoattractant.
The concepts and method of quantitation of these two characteristics of
chemoattractants are only beginning to be evaluated for hematopoietic
stem and progenitor cells. SLF showed chemotactic effects on mast cells
and small-cell lung cancer cell lines expressing
c-kit.23,24 Murine SLF has been reported to be a
chemotactic and chemokinetic factor for murine HPC. However, a role for
SLF as a chemoattractant for human HPC has not yet been
established.15
In this study, we examined the effects of SDF-1 and SLF on migration of
the growth factor-dependent human cell line MO7e and on human cord
blood (CB) and BM CD34+ cells using a two-chamber in vitro
migration system.25 The chemotactic and chemokinetic
activities of SDF-1 and SLF, alone and in combination, and in the
absence and presence of factors present in BM, CB, and PB plasma
allowed us, using a newly reported method to quantitate migration, to
suggest a model for HPC migration induced by gradients of
chemoattractants to and mobilization from the BM microenvironment.
| |
MATERIALS AND METHODS |
Cells.
Heparinized human CB was collected from healthy, full-term neonates
according to institutional guidelines immediately after vaginal
delivery. Human BM was collected from healthy donors after receiving
informed consent. CB and BM aspirates were diluted 1:3 with
phosphate-buffered saline (PBS) containing 2 mmol/L EDTA, pH 7.4
(Sigma, St Louis, MO). Diluted CB and BM cells were separated by
density gradient centrifugation on Ficoll-paque (1.077 g/mL) (Biochem
KG, Berlin, Germany). Mononuclear cells were resuspended in PBS
containing 0.5% bovine serum albumin (BSA) and 2 mmol/L EDTA at
3 × 108 cells/mL. These cells were further
processed by magnetic cell sorting (MACS)
CD34+ isolation kit (Miltenyi Biotec, Auburn, CA) to
positively select CD34+ cells. The purity of isolated
CD34+ cells was from 85% to 98%. The growth
factor-dependent myeloid cell line, MO7e, was maintained in RPMI-1640
medium supplemented with 20% fetal calf serum (FCS) (Hyclone
Laboratory, Logan, UT) and 100 U/mL GM-CSF. The biological
characteristics of this cell line have previously been
described.26,27 M2-10B4 (American Type Culture Collection,
Rockville, MD, CRL-1972), a mouse stromal cell line, was
maintained in RPMI 1640 containing 10% FCS.
Cytokines, chemokines, antibodies, and other reagents.
Chemically synthesized SDF-1 was a kind gift from Dr Ian Clark-Lewis
(University of British Colombia, Vancouver, Canada). Highly purified
recombinant human SLF, GM-CSF, and IL-3 were kind gifts from Immunex
Corp (Seattle, WA). Erythropoietin (EPO) was purchased from Amgen Corp
(Thousand Oaks, CA). Phycoerythrin (PE)-conjugated
anti-CD34 monoclonal antibody was purchased from Becton Dickinson (San
Jose, CA). TRI-COLOR-conjugated anti-c-kit monoclonal antibody was
purchased from CALTAG Laboratory (Burlingame, CA). Antihuman SLF
neutralizing antibody was purchased from R&D Systems (Minneapolis, MN).
Pertussis toxin was purchased from Sigma Chemical Co.
In vitro two-chamber migration assay.
Chemotaxis and chemokinesis were assayed by a modification of
checkerboard assay.25 One hundred microliters of chemotaxis
buffer (RPMI 1640, 0.5% crystallized deionized bovine serum albumin
[BSA; Calbiochem, San Diego, CA], and antibiotics) containing cells
were added to the upper chamber of a Costar Transwell (Cambridge, MA,
6.5 mm diameter, 5 µm pore; a 5 µm pore was shown in preliminary
experiments to be optimal for migration of MO7e and CD34+
cells in response to chemoattractants with low background migration),
and 0.6 mL of chemotaxis buffer was added to the lower chamber. 2.5
× 105 MO7e cells or 1 to 2 × 105
CD34+ cells were used for each Transwell. Various amounts
of chemoattractants or test plasmas were added to the chemotaxis buffer
in the upper and/or lower chamber to form various
chemoattractant concentration gradients. Positive gradient (0/+) was
made by adding chemoattractant to the lower chamber, negative (+/0)
gradient was made by adding chemoattractant to the upper chamber, and
zero gradient was made by either adding chemoattractant to both
chambers (+/+) or by not adding chemoattractant to either chamber
(0/0). Chambers were incubated at 37°C, 5% CO2 for 4
to 5 hours, or the indicated time periods. Cells migrating into the
lower chamber were counted using a FACscan (Becton Dickinson), with
appropriate gating, for 20 seconds at a high flow rate. Average cell
number and standard deviation was calculated from triplicated
experiments. The number of events acquired for 20 seconds was
approximately between 50 (medium) and 800 (SDF-1 + SLF)
(CD34+ cells), and 0 (medium) and 3,000 (SDF-1+ SLF) (MO7e
cells), when 2.5 × 105 MO7e cells/well or 1 to 2
× 105 CD34+ cells/well were added.
Percent migration was determined by calculating percentage of input
cells migrated into the lower chamber (average events for 20 seconds
/ average input cell events for 20 seconds × 100). For in
vitro mobilization experiments, indicated amounts of SDF-1 and SLF were
added with cells to the upper chamber to form a negative gradient of
chemoattractants, and mobilizing chemoattractants were added to the
lower chamber to mobilize cells from the upper chamber. For inhibition
of SDF-1 effects, MO7e cells were pretreated for 1 hour with pertussis
toxin (500 ng/mL) in the chemotaxis buffer. For blocking the effects of
SLF, anti-SLF antibody (10 µg/mL, final concentration) was added in
the upper and lower chambers of the migration system.
Preparation of BM, CB, and PB plasma for chemotaxis.
BM was aspirated from donors' iliac crest. BM aspirates and PB for
each experiment were obtained from the same donor within minutes of
each other. Heparinized BM, PB, and CB were centrifuged
(1,000g, 15 minutes, 25°C). Plasma supernatants were
collected and diluted twofold (final concentration) with chemotaxis
buffer for the chemotaxis experiments. BM and PB plasma obtained from
the same donor were used for each experiment to rule out individual
differences.
Actin polymerization assay.
This assay was performed according to the study by Howard and
Meyer28 with some modifications. MO7e cells were
resuspended in RPMI 1640 with 0.1% BSA at 1.25 × 106
cells/mL. SDF-1 (100 ng/mL) or SLF (10 µg/mL) was added to the cell
solution, and 0.4 mL cell solution was transferred to 0.1 mL
fluorescein isothiocyanate (FITC)-phalloidin solution (4 ×
10-7 mol/L FITC-labeled phalloidin, 0.5 mg/mL
1- -lysophosphatidylcholine, 18% formaldehyde in PBS, all from
Sigma Chemical Co) to stain and fix the cells. Cells were further
incubated for 10 minutes at 37°C, centrifuged, and resuspended in
0.5 mL of 1% paraformaldehyde solution. Mean fluorescence was measured
by FACscan (Becton Dickinson).
Colony-forming cell assays for HPC.
Migrated or input cells were plated at concentrations not exceeding 300
CD34+ cells/mL in 35-mm plastic tissue culture dishes
(Costar, Cambridge, MA) containing 1 U/mL recombinant
human (rhu) EPO, 100 U/mL rhu GM-CSF, 100 U/mL rhu IL-3, with or
without 50 ng/mL rhu SLF in 1.1% methylcellulose culture medium
containing 30% FBS.29,30 The cultures were incubated at
37°C in a 100% humidified atmosphere of 5% CO2 at
lowered (5%) O2. After 14 days of incubation, burst
forming unit-erythroid (BFU-E), and colony-forming unit-granulocyte
macrophage (CFU-GM) were scored from the plates containing IL-3,
GM-CSF, and EPO, and mixed cell (CFU-granulocyte erythroid macrophage
megakaryocyte [GEMM]) colonies were scored from the plate containing
IL-3, GM-CSF, EPO, and SLF. BFU-E, CFU-GM, and CFU-GEMM, which
respectively identify erythrocyte, granulocyte-macrophage, and
multipotential progenitor cells, were scored in situ with an inverted
microscope using standard criteria for their
identification.29,30
Measurement of kinetics of diffusion, migration, and
proliferation/survival effect of cytokines.
For diffusion experiments, SLF was added at final concentration of 10
ng/mL (600 µL in the chemotaxis buffer) to the lower chamber and
washed 2.5 × 105 MO7e cells (100 µL volume in the
chemotaxis buffer) were added to the upper chamber. At various time
points, contents from each chamber were collected and centrifuged to
separate cells from the buffer. Cells were fixed in 1%
paraformaldehyde and viable cell numbers were counted within 24 hours
by flow cytometry. Viable cells and dead cells were distinguished on
side scatter and forward scatter channels. Supernatants were stored at
 20°C until measurement of SLF concentration. SLF
concentration was determined by the Quantikine (R&D Systems). For
measurement of proliferation and survival effects of cytokines, 2.5
× 105 MO7e cells per well were added to 24-well
plates containing chemotaxis buffer with SDF-1 (100 ng/mL), SLF (10
ng/mL), or control medium. At various time points, MO7e cells were
harvested and fixed in 1% paraformaldehyde for viable cell counting by
flow cytometry.
Calcium flux responses in M07e cells.
MO7e cells washed with PBS were loaded with 2.5 µmol/L FURA-2 AM in
Hanks' balanced salt solution (HBSS) (Sigma Chemical Co),
pH 7.4, supplemented with 0.05% BSA at 37°C for 45 minutes, and
washed twice with PBS. FURA-2 AM-loaded cells were resuspended in HBSS
supplemented with 0.05% BSA at 5 × 106 cells/mL, and
placed in a continuously stirred cuvette at 37°C in a MSIII
fluorimeter (Photon Technology Inc, South Brunswick, NJ). Fluorescence
was monitored at 340 and 380 nm for excitation and 510 nm for emission.
The data were recorded as the relative ratio of fluorescence excited at
340 and 380 nm. Data were collected every 1 second. SDF-1 was used at a
final concentration of 50 nmol/L.
Statistics.
Results, shown as mean ± standard deviation (SD), are
representative of at least three different experiments. Significant
differences were determined by use of Student's t-test.
| |
RESULTS |
SDF-1 and SLF are efficient chemoattractants for MO7e cells and SLF,
but not SDF-1, has chemokinetic activity.
SDF-1 showed maximum cell attraction (over 30% MO7e cell migration)
around 100 ng/mL in a positive gradient (0/+) during a 4-hour
incubation period (Fig 1A). This optimum
concentration range for MO7e cells was similar to the reported
concentration for BM CD34+ cell chemotaxis.15
At 1,000 ng/mL, cell migration was significantly decreased from maximal
levels. SLF was also a good chemoattractant for MO7e cells. It usually
attracted more than 20% of input cells at 10 ng/mL optimum
concentration during a 4-hour incubation (Fig 1B). SLF-dependent MO7e
migration was decreased significantly at 100 ng/mL. We examined MO7e
cell migration over time up to 24 hours in the Transwell chemotaxis
system. SDF-1-dependent migration occurred only within 5 hours and
after 5 hours, no more migration was observed (Fig
2A). However, SLF-dependent migration
continuously increased during the 24-hour period (Fig 2A). We examined
cytokine diffusion in the Transwell chemotaxis system using SLF as a
model molecule. We added SLF at 10 ng/mL in the chemotaxis buffer to
the lower chamber (volume 600 µL) and 100 µL of the chemotaxis
buffer containing no SLF to the upper chamber, and measured SLF
concentration by enzyme-linked immunosorbent assay (ELISA) in both
chambers at different time points up to 24 hours. SLF concentrations in
the upper and lower chambers reached complete equilibrium at the
14-hour time point (Fig 2B). After 3 and 5 hours, respectively, the SLF
concentration of the upper chamber reached approximately half and 80%
of SLF concentration of the lower chamber (Fig 2B). To exclude the
possibility that the increased cell number in the lower chamber was due
to indirect effects of SDF-1 and SLF on survival and proliferation of
MO7e, we scored the viable cell number after incubation of MO7e cells
in the chemotaxis buffer containing SDF-1, SLF, and medium at different
time points. During the first 5-hour incubation, there is no difference
in viable cell numbers among MO7e cells incubated in SDF-1, SLF, or
medium (Fig 2C). After 5 hours, MO7e cells incubated in SLF slowly
increased in cell number, while MO7e cells incubated in SDF-1 or medium
began to decrease. There was 45% increase in MO7e cell number during a
19-hour incubation with SLF between the 5- and 24-hour time point (Fig
2C). However, the cell number scored by chemotaxis experiment increased
500% in response to SLF in the lower chamber during the same time
period (Fig 2A) suggesting most of the increased cell number in the
chemotaxis system was due to SLF-dependent cell migration rather than
proliferation. We noted that the 4- to 5-hour time point was the best
time point to study chemotaxis and chemokinesis because the indirect
effects of cytokines on a cell proliferation and survival were
negligible and the chemotaxis assay system maintained an effective
chemoattractant gradient during this period.
View larger version (12K):
[in this window]
[in a new window]
| Fig 1.
Differences in chemotactic and chemokinetic activities of
SDF-1 and SLF on MO7e cells. Dose-dependent induction of MO7e cell
migration into the lower chamber by (A) SDF-1 or (B) SLF in a positive
gradient (0/+) or in a zero gradient (+/+) formed by equal
concentration of SDF in both chambers.
|
|
View larger version (20K):
[in this window]
[in a new window]
| Fig 2.
Kinetics of MO7e cell migration, diffusion of SLF, and
survival/proliferation effects of SDF-1 and SLF. (A) MO7e cell
migration was monitored during 24 hours at indicated time points after
setting initial positive gradients with SDF-1 (100 ng/mL) and SLF (10
ng/mL). Viable cell numbers in the lower chambers were counted and the
average and range of duplicate were shown. (B) Diffusion of SLF from
the lower chamber to the upper chamber was monitored at indicated time
points. SLF (10 ng/mL) was added to the lower chambers of the Transwell
system to form a positive gradient. (C) MO7e cells were incubated in
24-well plates containing SLF (10 ng/mL), SDF-1 (100 ng/mL), or medium.
At indicated time points, viable MO7e cells were counted (see Materials
and Methods for details).
|
|
Chemokinetic activity can be defined as a chemoattractant's ability to
induce random cell migration under a zero chemoattractant gradient
(+/+). SLF, but not SDF-1, showed a strong chemokinetic effect on MO7e
cells in a zero gradient (+/+) (Fig 1A and B). A clearer picture of the
chemotactic activity of SDF-1 and the chemotactic and chemokinetic
activity of SLF can be seen by use of a modified checkerboard assay
shown in Table 1 and as described below.
We evaluated the ability of SLF and SDF-1 to reorganize actin
cytoskeleton in MO7e cells. SLF at 10 ng/mL, an optimum concentration
for chemotaxis, was an efficient inducer of actin polymerization (Fig
3). SDF-1 at 100 ng/mL, an optimum
concentration for chemotaxis, induced actin polymerization in MO7e
cells, similar to that reported in T cells by others16
where they used a higher concentration of SDF-1 (1,000 ng/mL). F-actin
polymerized by SLF depolymerized more slowly than that of SDF-1
demonstrating a difference in kinetics of actin reorganization.
Quantitation of chemotactic and chemokinetic activities.
To clarify the chemotactic and/or chemokinetic activities of
chemoattractants, we have proposed a number of different formulae to
quantitate and compare effects (Table 2)
that are based on the data in Table 1. SDF-1 had a maximum chemotactic
activity (MCTA) around 30% and the specific MCTA was about
0.3%/ng/mL. MCTA and specific MCTA of SLF were about 23% and
2.3%/ng/mL, respectively. Considering the molecular weights of the two
chemoattractants tested (SDF-1, 8 kD; SLF, 31 kD), SLF was
a far (25-fold) more efficient chemoattractant than SDF-1, although its
MCTA was lower than that of SDF-1. Maximum chemokinetic activity (MCKA)
of SLF was 16.3%, while that of SDF-1 was negligible. The
chemotactic-chemokinetic index (CCI) shows the relative ratio of
chemotactic activity to chemokinetic activity and can be used as
quantitative criteria to determine whether a chemoattractant is a pure
chemotactic factor or a chemotactic and chemokinetic factor. The CCI of
SDF-1 was 20 meaning its chemotactic activity is 20 times stronger than
its chemokinetic activity. CCI of SLF was 1.38 meaning its chemotactic
activity is comparable to its chemokinetic activity. Relative
chemokinetic activity (RCKA) is a figure to be used to assess the
relative chemokinetic activity of a chemoattractant to the chemotactic
activity. Lower RCKA, eg, less than 10%, suggests very low
chemokinetic activity, while RCKA close to 100% suggests very high
chemokinetic activity. Overall, these quantitations demonstrated that
SDF-1 was a chemotactic, but not a chemokinetic factor, while SLF had
both chemotactic and chemokinetic activities.
Effects of SDF-1 and SLF on CD34+ cells.
To better evaluate the relevance of the chemotactic effects of SDF-1
and SLF, we examined the effects of SLF and SDF-1 on CB and BM
CD34+ cells. It has been reported that mouse SLF is both
chemotactic and chemokinetic for mouse HPC.10 It was also
reported that human SLF might not have any chemotactic activity toward
human CD34+ cells.15 By counting the migrated
cell number, the chemotactic effect of SLF was barely detectable on
CD34+ cells (Fig 4A). However,
the HPC colony-forming assay of migrated cells clearly showed the
chemotactic effect of SLF on HPC on the total CD34+ cell
population (Fig 4B). SLF attracted about 5% to 15% of HPC from input
CD34+ cells within 5 hours. Because Okumura et
al10 observed that murine SLF attracted murine HPC at 12-
and 24-hour time points, we also examined the chemotactic effects of
SLF on human HPC at a longer time point (14 hours). After 14 hours,
SLF-dependent HPC migration reached up to 30%, which was twofold of
that which occurred after 5 hours, and the optimal concentration of SLF
for HPC attraction was about 50 ng/mL (data not shown). This appeared
to be due to SLF-dependent migration not being sensitive to breakdown
of the chemoattractant gradient, which can continue even after
equilibration of SLF in both chambers (Fig 2A and B). We did all other
HPC chemotaxis experiments using a 5-hour readout system. As shown in
Fig 5A and B, SDF-1 is a strong chemotactic
factor for human CD34+ cells, similar to that reported by
others.15 In this context, when added together with SDF-1
to the in vitro migration system, SLF significantly increased
SDF-1-dependent chemotaxis of CB and BM CD34+ cells during
a 5-hour migration period (Fig 5A and B). The cooperativity between
SDF-1 and SLF for HPC attraction was demonstrated by colony-forming
cell assays (Fig 5C).
View larger version (38K):
[in this window]
[in a new window]
| Fig 4.
Chemotactic activity of SLF on HPC. Migration of cells
into the lower chamber was assessed by either total CD34+
cell counting (A) or HPC colony-forming cell assay (B) SLF (50 ng/mL)
was added to the lower chamber to attract CB CD34+ cells
for 5 hours. *Significant difference from control, P < .02.
|
|
View larger version (28K):
[in this window]
[in a new window]
| Fig 5.
Combined effects of SDF-1 and SLF on CB
CD34+ (A), BM CD34+ (B) and CB HPC cells.
Cells migrated into the lower chamber were counted (A and B) or assayed
for HPC (C) after the indicated chemoattractants (SDF-1 at 100 ng/mL
for part A and B, 50 ng/mL for part C; SLF at 50 ng/mL for part A, B,
and C) or control medium were added singly or in combination to either
the upper or lower chambers. *Significant difference from controls
(second bar to the left for part A and B, and medium for part C,
P < .05). **Significant change from migration induced by
either SLF or SDF-1 alone, P < .005.
|
|
Combined chemotactic effects of SDF-1 and SLF on MO7e cells.
We evaluated the combined effects of SDF-1 and SLF in a positive
gradient using MO7e cells as a model system because this cell line
responded well to both SDF-1 and SLF (Tables 1 and 2, Fig 1). As shown
in Fig 6A, the combination of SDF-1 and SLF
induced additive effects. This suggested that SDF-1-dependent
chemotaxis was not redundant or overlapping with SLF-dependent
chemotaxis and that these two chemoattractants might cooperate in
inducing MO7e cell migration. The additive effect was apparent within
the range of the different concentrations of SDF-1 and SLF assessed
(Fig 6B).
View larger version (38K):
[in this window]
[in a new window]
| Fig 6.
Combined effects of SDF-1 and SLF on MO7e cells.
Migration of cells into the lower chamber after (A) SLF(10 ng/mL)
and/or SDF-1 (100 ng/mL) were added to the lower chamber, or
(B) SDF-1 and/or SLF were added to the lower chamber in
combination at different concentrations (shown in ng/mL). *Significant
difference from the second or third bar to the left, P <
.05.
|
|
SDF-1 in a negative gradient inhibits SDF-1- and SLF-dependent
chemotaxis and chemokinesis.
The presence of SDF-1 in the lower chamber (a positive gradient; 0/+)
induced cell migration into the lower chamber, while negative (+/0) or
zero (+/+) gradient did not attract cells (Table 1).
These observations led us to hypothesize that SDF-1 in the upper
chamber might inhibit the migration of cells into the lower chamber. We
tested this inhibitory effect of SDF-1 on SLF-dependent migration of
MO7e cells. SDF-1 (100 ng/mL) in the upper chamber decreased
SLF-dependent migration occurring at its most effective concentration
(10 ng/mL SLF for MO7e cells) by 40% to 50% (Fig
7). However, SLF in the upper chamber had
no inhibitory effect on SDF-1-dependent migration, even though it
inhibited the migration of SLF-itself (Fig 7). Many chemokines are
known to desensitize their receptors so that cells are unable to
further react to the chemokines. A negative concentration gradient of
SDF-1 is an effective condition for SDF-1 to bind cells and thus an
efficient desensitization condition. In this context, we examined
desensitization of calcium mobilization by SDF-1. As shown in Fig
8, an initial SDF-1 treatment abolished
MO7e cells' ability to induce calcium mobilization by a second
treatment with SDF-1. So it is possible that SDF-1 in the upper chamber
may desensitize M07e cells, and the desensitized cells cannot be
attracted to SDF-1 in the lower chamber.
View larger version (31K):
[in this window]
[in a new window]
| Fig 7.
Inhibitory effects of SDF-1 or SLF in the upper chamber
on MO7e cell migration with SDF-1 and/or SLF in the lower
chamber. SDF-1 (100 ng/mL), SLF (10 ng/mL), and/or control
medium were added to either the upper or lower chamber as indicated.
Significant difference between bars, a and b (P < .01), a and
c (P < .02), d and e (P < .002), and d
and f (P < .0002).
|
|
View larger version (30K):
[in this window]
[in a new window]
| Fig 8.
Desensitization of calcium mobilization in MO7e cells by
SDF-1. SDF-1 (final concentration of 50 nmol/L) was used to activate
MO7e cells at the indicated time points.
|
|
SDF-1, a poor mobilizer by itself, is an effective comobilizer for
SLF.
We used the in vitro migration system for MO7e cells to study the
concept of mobilization. The two chemoattractants, SDF-1 and SLF, were
added together to the upper chamber to form a negative inhibitory
concentration gradient (Fig 9A and B). The
rationale for this experiment was based on a hypothesis that the
hematopoietic environment would produce and keep chemoattractants
inside the BM microenvironment to inhibit unwanted mobilization of HPC
into the PB system by continuously attracting them to the BM. SDF-1,
added to lower chamber at 100 ng/mL in this in vitro mobilization
system, mobilized less than 2% MO7e cells from the SDF-1 (100 ng/mL)
and SLF (10 ng/mL)-containing upper chamber, showing that the
environment formed by the two chemoattractants in the upper chamber
greatly inhibited SDF-1-(in lower chamber)-dependent migration (Fig
9A). In a positive gradient without this inhibitory negative gradient,
SDF-1 (100 ng/mL) usually attracted more than 30% MO7e cells (Fig 1A).
SLF, known to be an effective HPC mobilizer in mice and nonhuman
primates, when added to lower chamber at 10 ng/mL, mobilized fourfold
more MO7e cells than SDF-1 (Fig 9A). When added together to the lower
chamber, SDF-1 increased the SLF-dependent mobilization significantly,
in a far greater than additive fashion (Fig 9A). Because SDF-1 at 100
ng/mL is a relatively high concentration and a maximum dose for
chemotaxis, we reduced the concentration of SDF-1 in the upper chamber
to 20 ng/mL (Fig 9B), while maintaining the concentration of SLF in the
upper chamber at 10 ng/mL, a maximally effective dose; SDF-1 still
showed a strong antimobilization effect in a negative gradient (+/0) at
this lower concentration. At this lower SDF-1 concentration in the
upper chamber, we observed a similar enhancement of SLF-dependent MO7e
mobilization by 20 ng/mL of SDF-1 in lower chamber (Fig 9B). As we
increased the SDF-1 concentration in the lower chamber in this in vitro
mobilization system, SLF-dependent mobilization was greatly enhanced by
the added SDF-1 in the lower chamber (Fig 9B). Pertussis toxin, a
G-protein coupled receptor inhibitor, did not block SLF-dependent
migration, while it did block SDF-1-dependent migration in a
preliminary experiment. Thus, we used pertussis toxin to determine if
SDF-1 binding to its G-protein-coupled receptor was responsible for
these effects. The comobilization activity of SDF-1 was inhibited by
pretreatment of MO7e cells by pertussis toxin (Fig 9C), showing that
this comobilization activity is mediated by specific signaling from a
G-protein coupled receptor, most likely CXCR-4.19 Anti-SLF
neutralizing antibody was used to show that the SLF-dependent migration
was specific to added SLF (Fig 9C).
View larger version (26K):
[in this window]
[in a new window]
| Fig 9.
Model of in vitro mobilization by SDF-1 and SLF. (A)
SDF-1 (100 ng/mL) and SLF (10 ng/mL) were added to the upper chamber to
form a negative concentration gradient and SDF-1 (100 ng/mL)
and/or SLF (10 ng/mL) were added to the lower chamber to
mobilize MO7e cells from the upper chamber. (B) The concentration of
SDF-1 at a lower concentration (20 ng/mL) with optimal concentration of
SLF (10 ng/mL) was added to the upper chamber to form a less severe
negative gradient of chemoattractants. SDF-1 at various concentrations
(0, 20, 100, and 1,000 ng/mL) and SLF (10 ng/mL) were added to the
lower chamber to mobilize the MO7e cells from the upper to the lower
chamber. (C) Anti-SLF neutralizing antibody (10 µg/mL) and pertussis
toxin (500 ng/mL) were used to respectively inhibit the effects of SLF
and SDF-1 on migration of MO7e cells. SLF (10 ng/mL) and/or
SDF-1 (100 ng/mL) was added to the lower chamber. SLF (10 ng/mL)
and/or SDF-1 (20 ng/mL) was added to the upper chamber. *
Designates significant changes from control (P < .02). ** 0%
migration.
|
|
The BM environment has chemotactic activity toward human HPC cells.
We evaluated the possibility that the BM microenvironment could have
chemotactic activity on HPC against the PB system. We examined plasma
from BM, CB, and PB for chemotactic activity. BM plasma, but not PB or
CB plasma, showed significant chemotactic activity on human BM
CD34+ cells (Fig 10A). It has
been reported that mouse stromal cell lines express chemotactic factors
for HPC.31 We included here the culture supernatants of
mouse BM stromal cell line, M2-10B4, as a control and observed the
culture supernatants had chemotactic effects on human CD34+
cells. The sensitivities of CB and BM CD34+ cells to the BM
plasma were not significantly different from each other (data not
shown). BM plasma caused the migration of BFU-E, CFU-GM, and CFU-GEMM
(Fig 10B). The lower chamber BM plasma attracted less CD34+
cells when it was antagonized by the same BM plasma in the upper
chamber showing a low chemokinetic activity of the BM plasma (Fig 10C).
View larger version (41K):
[in this window]
[in a new window]
| Fig 10.
Chemotactic and chemokinetic activities of the BM plasma
on CD34+ cells. (A) Comparison of chemotactic activity of
plasma from BM, CB, and PB on migration of BM CD34+ cells
from the upper to lower chamber. Each plasma sample was diluted 1:2 and
added to lower chamber. SUP is conditioned medium from the mouse
stromal cell line, M2-10B4. (B) Chemotactic activity of BM plasma for
human CB HPC present in a CD34+ population of cells. (C)
Chemotactic and chemokinetic activity of BM plasma against PB plasma on
CB CD34+ cells. PB and BM plasma used were diluted 1:2.
(D) Inhibitory effect of the negative gradient of BM plasma on BM
CD34+ cell migration induced by SDF-1. Diluted PB plasma
(1:2) containing SDF-1 (50 ng/mL) was added to the lower chamber to
attract human BM CD34+ cells from the upper chamber
containing the indicated diluted plasma. *Significant changes from
controls (medium for part A, PB for part B, PB/PB for part C, and third
bar (PB/PB+SDF) to the left), P < .01.
|
|
Antimobilization effect of BM plasma in a negative gradient and
mobilization of CD34+ cells from the effects of BM plasma
by SDF and SLF.
We next tested a model that the BM environment may form a negative
chemoattractant gradient for BM HPC to retain HPC within the BM. We set
up an experiment such that BM plasma and CD34+ cells in the
upper chamber and PB plasma in the lower chamber would mimic the in
vivo BM and PB systems in terms of a chemotactic gradient. When we
added SDF-1 in the lower chamber to induce migration, BM plasma in the
upper chamber inhibited SDF-1-dependent cell migration into the lower
chamber, suggesting an inhibitory negative chemoattractant gradient of
the BM environment on HPC mobilization into the PB system (Fig 10D). We
also examined the effect of SDF-1 and SLF on CD34+ cell
mobilization into the lower chamber in this system. SDF-1 in the lower
chamber (50 ng/mL) mobilized about 15% of input CD34+
cells from this BM chemotactic environment, and SLF (50 ng/mL)
increased the SDF-1-dependent mobilization by about 25% (data not
shown).
| |
DISCUSSION |
The use of the formulae shown in Table 2 now allows a quantitative
evaluation of the chemotactic versus chemokinetic activities of various
effector molecules. This type of quantitative evaluation has not been
previously applied to characterize chemoattractant molecules. This
information should be of value in evaluating and comparing activities
of multiple chemoattractants for a type of cells. Differences in the
chemotactic and chemokinetic activities of SDF-1 and SLF suggest
possible interacting roles of two chemoattractants in the migration of
HPC. SDF-1 is a chemotactic factor that induces migration of cells and
the direction of cell movement is determined by the concentration
gradient of SDF-1. To our surprise, even low concentrations (eg, 1
ng/mL) of SDF-1 in a negative gradient could inhibit the effects of a
positive gradient-dependent migration. This characteristic of SDF-1
suggests a possible important role for SDF-1 as a physiologic
antimobilizing factor that under normal conditions may restrain the
mobilization of HPC out of BM.
The in vitro chemotaxis system used in this study consists of two
chambers, an upper (100 µL) and a lower (600 µL) chamber. Pores of
the membrane (5 µm in diameter) separating the two chambers are
smaller than most cells. However, it is big enough for small cytokines
such as SDF-1 and SLF to diffuse from one chamber to the other. Because
the upper chamber is relatively smaller than the lower chamber, the
cytokine concentration in the lower chamber does not change much, while
that of the upper chamber increases over time. It took 15 hours for a
cytokine (SLF at 10 ng/mL was used in this study) to reach equalibrium
by diffusion from the lower chamber to the upper chamber (Fig 2B).
However, effective gradients of chemotactic factors for cell migration
seem to be lost more quickly. SDF-1-dependent migration stopped after
5 hours when the two chambers were believed to lose much of their
concentration difference. SLF induced consistent cell migration
independently of diffusion and loss of a SLF concentration gradient.
These results are in good agreement with the checkerboard assay
experiments, where chemotactic and chemokinetic SLF induced cell
migration in both positive (0/+) and zero (+/+) gradients, while
chemotactic SDF-1 induced only in a positive gradient.
The mechanisms underlying cell movement in response to
chemoattractants has not been clearly established. Small
guanosine 5 -triphosphate (GTPase) molecules
such as rho-like GTPases, Rac1 and 2, and CDC42Hs and actin regulation
proteins, such as Wiskott-Aldrich syndrome protein and other actin
binding proteins, have been suggested to be involved in cytoskeletal
reorganization for formation of filopodia, lamellipodia, and stress
fibers, important processes for cell movement.32,33 There
is evidence that signals from tyrosine kinase via adapter protein NCK,
and from G-protein-coupled receptors may regulate these actin
regulation proteins.34,35 The receptor for SDF-1 is CXCR4,
a G-protein-coupled receptor, and the receptor for SLF is c-kit, a
receptor protein tyrosine kinase. It will be of interest to determine
whether these small intracellular molecules are involved in
receptor-mediated migration of stem and progenitor cells to the BM and
mobilization out of the BM. In this context, it is of interest that
actin polymerization induced by SDF-1 and SLF were different from each
other in terms of kinetics (Fig 3). It remains to be determined whether
the relatively slower kinetics of actin depolymerization is directly
related to the chemokinetic nature of SLF-induced cell migration.
A possible problem in interpretation of experiments using primary
CD34+ cells is the purity and possible roles of other cells
in the cell population. BM and CB CD34+ cells used in this
study were respectively 95% and 90% pure on average. We cannot
rigorously rule out the possibility that SDF-1 and SLF might have
indirect effects on cell migration by the induction and release of
other cytokines from non-CD34+ cells or even
CD34+ cells. However, these effects would have to be
relatively rapid in terms of cytokine induction and diffusion and a
response to the initial test cytokine. Chemoattractants are often
believed to act in a microenvironment or on the surface of endothelial
cell layers. SDF-1 has a high isoelectric point (10.9) and affinity for
heparin.16 Although it has not been reported what
concentrations of chemoattractants exist in these environments, BM
stromal cells produce SDF-1 up to 800 ng/mL.16 It is
reasoned that these surface or trapped chemoattractants in the
microenvironment can form quite high chemoattractant concentrations.
The optimal concentration for most chemokines as assessed in vitro are
within a range from 10 to 1,000 ng/mL in the transwell chemotaxis
system. We used 100 ng/mL SDF-1 for most experiments because this
was an optimal amount of SDF-1.
SLF was reported to have both chemotactic and chemokinetic effects on
murine HPC,10 but not on human PB and CB CD34+
cells.15 However, the chemotactic activity of SLF on human
CD34+ cells was assessed by counting total cell number, but
not by functional assay. We observed that it was difficult to assess
the chemoattractant effect of SLF by cell counting due to specificity
of SLF for subtypes of CD34+ cells. We demonstrated by
functional HPC colony assay that SLF has chemotactic activity on HPC
and this effect is time-related and may be more specific for
colony-forming HPC in contrast to a total population of
CD34+ cells. We tried to examine whether c-kit-expressing
CD34+ cells are better attracted to SLF than
c-kit-negative cells. However, this was not possible because SLF did
not attract enough CD34+ cells for immunostaining and flow
cytometric analysis. Both SDF-1 and SLF showed no specificity for any
particular colony-forming HPC and attracted all BFU-E, CFU-GM, and
CFU-GEMM tested. However, it is possible that there may be
uncharacterized chemoattractants specific for each type of
colony-forming HPC. For T-cell subtypes, some chemokines showed
specificity for certain subtypes of T cells, such as
CD45RO+ memory cells or CD4+ helper T
cells.36-38
It had not been previously reported that multiple chemoattractants
could cooperatively affect cell migration. When added together to the
lower chamber of the in vitro chemotaxis system to form a positive
gradient (0/+), SDF-1 and SLF induced cell migration additively (Fig 6A
and B). This result is of interest in that cells under the influence of
"optimum" concentrations of one chemoattractant for cell
migration still have the capacity to respond to the action of
"optimum" concentrations of another chemoattractant. This
additivity of two-chemoattractant-dependent migration was observed at
different concentrations of these two chemoattractants.
Chemotactic effects of SDF-1 and SLF manifested an interesting
phenomenon. When in a negative gradient, these chemotactic factors
inhibited cell migration induced by a positive gradient of these
chemoattractants (Table 1, and Fig 7). A possible explanation for this
inhibition could be that the added chemoattractant in the upper chamber
broke down the required stiffness of a positive chemoattractant
gradient formed by the chemoattractant in the lower chamber. Another
possibility is that the presence of SDF-1 in a negative gradient (+/0),
thus binding to its receptors on cells, desensitizes the cell's
ability to react to the chemoattractant in a positive gradient (0/+).
We examined this desensitization effect of SDF-1 on MO7e cells by
measuring calcium mobilization in response to SDF-1 treatment (Fig 8).
An initial SDF-1 treatment abolished cells' ability to mobilize
calcium when they were treated again by SDF-1. It is of interest that
the inhibition of cell migration was observed between two different
chemoattractants (Fig 7). SDF-1 in the upper chamber inhibited
SLF-dependent migration, while SLF was inhibitory to only SLF itself,
but had no effect on SDF-1-dependent migration. It appears that the
effects of SDF-1 are dominant over SLF in the inhibition. This
relationship between two chemoattractants suggests again the importance
of SDF-1 as a possible antimobilizing factor for HPC mobilization. So
it is conceivable that SDF-1 in the BM environment may attract HPC from
the PB system and inhibit mobilization of HPC out of BM.
In the BM, many cytokines and chemoattractants, secreted from stromal
cells or other accessory cells, are believed to form a suitable
physiologic environment for HPC migration, proliferation, and
differentiation.31,39 Chemoattractants may be especially
important in guiding HPC to its suitable microenvironment as suggested
in the diagram in Fig 11. Although it is
not known how much SDF-1 and SLF exist in the BM environment, it is
reasonable to think that these chemoattractants form various
concentration gradients over the blood system and the BM
microenvironment, attract HPC, and retain them in the BM
microenvironment, unless, as shown in Fig 11, this attraction is broken
by administered or induced effector molecules in the blood.
View larger version (33K):
[in this window]
[in a new window]
| Fig 11.
A model for homing and peripheralization of HPC by
chemoattractants. This model considers: (A) homing of HPC to
chemoattractants in the BM microenvironment and (B) mobilization of HPC
out of the BM microenvironment when the negative gradient of the BM is
broken by administering chemoattractants or known HPC mobilizers, which
may act directly or induce expressions of chemoattractants outside of
BM disturbing normal chemoattractant gradient around BM-PB system. The
presence and concentration of chemoattractants are represented as
intensity of gradient in the BM and PB compartment. Direction and size
of arrows crossing two compartments respectively indicate the direction
of cell migration and relative intensity of migration.
|
|
| |
FOOTNOTES |
Submitted June 17, 1997;
accepted August 28, 1997.
Supported by public health service grants, R01 HL 56416, R01 HL 54037,
and by a project in P01 HL 53586 from the National Institutes of
Health, Bethesda, MD (to H.E.B.).
Address reprint requests to Hal E. Broxmeyer, PhD,
Department of Microbiology/Immunology and the Walther Oncology Center,
Indiana University School of Medicine, 975 W Walnut St, Indianapolis,
IN 46202-5121.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Dr Ian Clark-Lewis for the generous gift of SDF-1.
| |
REFERENCES |
1.
Osogoe B,
Omura K:
Transplantation of hematopoietic tissue with the circulating blood.
Anat Rec
108:663,
1950
2.
Tavassoli M:
The marrow-blood barrier.
Br J Haematol
41:297,
1979[Medline]
[Order article via Infotrieve]
3.
Hendrikx PJ,
Martens ACM,
Hagenbeek A,
Keij JF,
Visser JWM:
Homing of fluorescently labeled murine hematopoietic stem cells.
Exp Hematol
24:129,
1996[Medline]
[Order article via Infotrieve]
4.
Turner ML,
Sweetenham JW:
Haematopoietic progenitor homing and mobilization.
Br J Haematol
94:592,
1996[Medline]
[Order article via Infotrieve]
5.
Hardy CL:
The homing of hematopoietic stem cells to the bone marrow.
Am J Med Sci
309:260,
1995[Medline]
[Order article via Infotrieve]
6.
Siena S,
Bregni M,
Brando B,
Ravagnani F,
Bonadonna G,
Gianni AM:
Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: Enhancement by intravenous recombinant granulocyte-macrophage colony-stimulating factor.
Blood
74:1905,
1989[Abstract/Free Full Text]
7.
Duhrsen U,
Villeval JL,
Boyd J,
Kannourakis G,
Morstyn G,
Metcalf D:
Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients.
Blood
72:2074,
1988[Abstract/Free Full Text]
8.
Drize N,
Chertkov J,
Samoilina N,
Zander A:
Effect of cytokine treatment (granulocyte colony-stimulating factor and stem cell factor) on hematopoiesis and the circulating pool of hematopoietic stem cells in mice.
Exp Hematol
24:816,
1996[Medline]
[Order article via Infotrieve]
9.
Donahue RE,
Kirby MR,
Metzger ME,
Agricola BA,
Sellers SE,
Cullis HM:
Peripheral blood CD34+ cells differ from bone marrow CD34+ cells in Thy-1 expression and cell cycle status in nonhuman primates mobilized or not mobilized with colony-stimulating factor and/or stem cell factor.
Blood
87:1644,
1996[Abstract/Free Full Text]
10.
Okumura N,
Tsuji K,
Ebihara Y,
Tanaka I,
Sawai N,
Koike K,
Komiyama A,
Nakahata T:
Chemotactic and chemokinetic activities of stem cell factor on murine hematopoietic progenitor cells.
Blood
87:4100,
1996[Abstract/Free Full Text]
11.
Jiang W,
Zhou P,
Kahn SM,
Tomita N,
Johnson MD,
Weinstein IB:
Molecular cloning of TPAR1, a gene whose expression is repressed by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA).
Exp Cell Res
215:284,
1994[Medline]
[Order article via Infotrieve]
12.
Tashiro K,
Tada H,
Heilker R,
Shirozu M,
Nakano T,
Honjo T:
Signal sequence trap: A cloning strategy for secreted proteins and type I membrane proteins.
Science
261:600,
1993[Abstract/Free Full Text]
13.
Nagasawa T,
Kikutani H,
Kishimito T:
Molecular cloning and structure of a pre-B-cell growth-stimulating factor.
Proc Natl Acad Sci USA
91:2305,
1994[Abstract/Free Full Text]
14.
Shirozu M,
Nakano T,
Inazawa J,
Tashiro K,
Tada H,
Shinohara T,
Honjo T:
Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene.
Genomics
28:495,
1995[Medline]
[Order article via Infotrieve]
15.
Aiuti A,
Webb IJ,
Bleul C,
Springer T,
Gutierrez-Ramos JC:
The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood.
J Exp Med
185:111,
1997[Abstract/Free Full Text]
16.
Bleul C,
Fuhlbrigge RC,
Casasnovas JM,
Aiuti A,
Springer TA:
A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1).
J Exp Med
184:1101,
1996[Abstract/Free Full Text]
17.
Nagasawa T,
Hirota S,
Tachibana K,
Takakura N,
Nishikawa S-i,
Kitamura Y,
Yoshida N,
Kikutani H,
Kishimoto T:
Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.
Nature
382:635,
1996[Medline]
[Order article via Infotrieve]
18.
Loetscher M,
Geiser T,
O'Reilly T,
Zwahlen R,
Baggiolini M,
Moser B:
Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes.
J Biol Chem
269:232,
1994[Abstract/Free Full Text]
19.
Oberlin E,
Amara A,
Bachelerie F,
Bessia C,
Virelizier J-L,
Arenzana-Seisdedos F,
Schwartz O,
Heard J-M,
Clark-Lewis I,
Legler DF,
Loetscher M,
Baggiolini M,
Moser B:
The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.
Nature
382:833,
1996[Medline]
[Order article via Infotrieve]
20.
Bleul CC,
Farzan M,
Choe H,
Parolin C,
Clark-Lewis I,
Sodroski J,
Springer TA:
The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV entry.
Nature
382:829,
1996[Medline]
[Order article via Infotrieve]
21.
Lapham CK,
Ouyang J,
Chandrasekhar B,
Nguyen NY,
Dimitrov DS,
Golding H:
Evidence for cell surface association between fusin and the CD4-gp120 complex in human cell lines.
Science
274:602,
1996[Abstract/Free Full Text]
22.
Endres MJ,
Clapham PR,
Marsh M,
Ahuja M,
Turner JD,
McKnight A,
Thomas JF,
Stoebenau-Haggarty B,
Choe S,
Vance PJ,
Wells TNC,
Power CA,
Sutterwala SS,
Doms RW,
Landau NR,
Hoxie JA:
CD4-independent infection by HIV-2 is mediated by fusin/CXCR4.
Cell
87:745,
1996[Medline]
[Order article via Infotrieve]
23.
Meininger CJ,
Yano H,
Rottapel R,
Bernstein A,
Zsebo KM,
Zetter BR:
The c-kit receptor ligand function as a mast cell chemoattractant.
Blood
79:958,
1992[Abstract/Free Full Text]
24.
Sekido Y,
Takahashi T,
Ueda R,
Takahashi M,
Suzuki H,
Nishida K,
Tsukamoto T,
Hide T,
Shimokata K,
Zsebo KM,
Takahashi T:
Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene.
Cancer Res
53:1709,
1993[Abstract/Free Full Text]
25.
Zigmond SH,
Hirsch JG:
Leukocyte locomotion and chemotaxis.
J Exp Med
137:387,
1973[Abstract]
26.
Hendrie PC,
Miyazawa K,
Yang Y-C,
Langefeld CD,
Broxmeyer HE:
Mast cell growth (c-kit ligand) enhances cytokine stimulation of proliferation of the human factor-dependent cell line.
Exp Hematol
19:1031,
1991[Medline]
[Order article via Infotrieve]
27.
Avanzi GC,
Lista P,
Giovinazzo B,
Miniero R,
Saglio G,
Benetton G,
Coda R,
Cattoretti G,
Pegoraro L:
Selective growth response to IL3 of a human leukemic cell line with megakaryoblastic features.
Br J Haematol
69:359,
1988[Medline]
[Order article via Infotrieve]
28.
Howard TH,
Meyer WH:
Chemotactic peptide modulation of actin assembly and locomotion.
J Cell Biol
98:1265,
1984[Abstract/Free Full Text]
29.
Broxmeyer HE,
Douglas GW,
Hangoc G,
Cooper S,
Bard J,
English DK,
Arny M,
Thomas L,
Boyse EA:
Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells.
Proc Natl Acad Sci USA
86:3828,
1989[Abstract/Free Full Text]
30.
Broxmeyer HE,
Hangoc G,
Cooper S,
Ribeiro R,
Graves V,
Yoder M,
Wagner J,
Vadhan-Raj S,
Benninger L,
Rubinstein P,
Broun ER:
Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults.
Proc Natl Acad Sci USA
89:4109,
1992[Abstract/Free Full Text]
31.
Yasumizu CR,
Toki J,
Asou H,
Nishino T,
Komatsu Y,
Ikehara S:
Production of hematopoietic stem cell-chemotactic factor by bone marrow stromal cells.
Blood
83:964,
1994[Abstract/Free Full Text]
32.
Nobes CD,
Hall A:
Rho, Rac, and CDC42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellopodia, and filopodia.
Cell
81:53,
1995[Medline]
[Order article via Infotrieve]
33.
Symons M,
Derry JMJ,
Kariak B,
Jiang S,
Lemahieu V,
McCormick F,
Francke U,
Abo A:
Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization.
Cell
84:723,
1996[Medline]
[Order article via Infotrieve]
34.
Rivero-Lezcano OM,
Marcilla A,
Sameshima JH,
Robbins KC:
Wiskott-Aldrich syndrome protein physically associated with Nck through Src homology 3 domains.
Mol Cell Biol
15:5725,
1995[Abstract]
35.
Kozma R,
Ahmed S,
Best A,
Lim L:
The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in swiss 3T3 fibroblasts.
Mol Cell Biol
15:1942,
1995[Abstract]
36.
Qin S,
LaRosa G,
Campbell JJ,
Smith-Heath H,
Kassam N,
Shi X,
Zeng L,
Buthcher EC,
Mackay CR:
Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential.
Eur J Immunol
3:640,
1996
37.
Schall TJ,
Bacon K,
Toy KJ,
Goeddel DV:
Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES.
Nature
347:669,
1990[Medline]
[Order article via Infotrieve]
38.
Schall TJ,
Bacon K,
Camp RD,
Kaspari JW,
Goeddel DV:
Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes.
J Exp Med
177:1821,
1993[Abstract/Free Full Text]
39.
Wolf NS,
Trentin JJ:
Hematopoietic colony studies. V. Effects of hematopoietic organ stroma on differentiation of pluripotent stem cells.
J Exp Med
127:205,
1968[Abstract]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. K. Kim, H.-N. Pak, J. H. Park, J. I. Choi, M.-H. Nam, Y. Jo, and Y.-H. Kim
Non-ischaemic titrated cardiac injury caused by radiofrequency catheter ablation of atrial fibrillation mobilizes CD34-positive mononuclear cells by non-stromal cell-derived factor-1{alpha} mechanism
Europace,
July 9, 2009;
(2009)
eup185v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Grassinger, D. N. Haylock, M. J. Storan, G. O. Haines, B. Williams, G. A. Whitty, A. R. Vinson, C. L. Be, S. Li, E. S. Sorensen, et al.
Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with {alpha}9{beta}1 and {alpha}4{beta}1 integrins
Blood,
July 2, 2009;
114(1):
49 - 59.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Hoggatt, P. Singh, J. Sampath, and L. M. Pelus
Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation
Blood,
May 28, 2009;
113(22):
5444 - 5455.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Foguenne, I. Di Stefano, O. Giet, Y. Beguin, and A. Gothot
Ex vivo expansion of hematopoietic progenitor cells is associated with downregulation of {alpha}4 integrin- and CXCR4-mediated engraftment in NOD/SCID {beta}2-microglobulin-null mice
Haematologica,
February 1, 2009;
94(2):
185 - 194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Jin, Y. Tabe, S. Konoplev, Y. Xu, C. E. Leysath, H. Lu, S. Kimura, A. Ohsaka, M.-B. Rios, L. Calvert, et al.
CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells
Mol. Cancer Ther.,
January 1, 2008;
7(1):
48 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Abraham, K. Biyder, M. Begin, H. Wald, I. D. Weiss, E. Galun, A. Nagler, and A. Peled
Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-Benzoyl-TN14003
Stem Cells,
September 1, 2007;
25(9):
2158 - 2166.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Fukuda, H. Bian, A. G. King, and L. M. Pelus
The chemokine GRO{beta} mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment
Blood,
August 1, 2007;
110(3):
860 - 869.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y N Kallis, M R Alison, and S J Forbes
Bone marrow stem cells and liver disease
Gut,
May 1, 2007;
56(5):
716 - 724.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Balasubramaniam, C. F. Mervis, A. M. Maxey, N. E. Markham, and S. H. Abman
Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia
Am J Physiol Lung Cell Mol Physiol,
May 1, 2007;
292(5):
L1073 - L1084.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. L.T. Ballard and J. M. Edelberg
Stem Cells and the Regeneration of the Aging Cardiovascular System
Circ. Res.,
April 27, 2007;
100(8):
1116 - 1127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Forde, B. J. Tye, S. E. Newey, M. Roubelakis, J. Smythe, C. P. McGuckin, R. Pettengell, and S. M. Watt
Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells
Blood,
March 1, 2007;
109(5):
1825 - 1833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Rossi, R. Manfredini, F. Bertolini, D. Ferrari, M. Fogli, R. Zini, S. Salati, V. Salvestrini, S. Gulinelli, E. Adinolfi, et al.
The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration
Blood,
January 15, 2007;
109(2):
533 - 542.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Panopoulos, L. Zhang, J. W. Snow, D. M. Jones, A. M. Smith, K. C. El Kasmi, F. Liu, M. A. Goldsmith, D. C. Link, P. J. Murray, et al.
STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils
Blood,
December 1, 2006;
108(12):
3682 - 3690.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Pirson, F. Baron, N. Meuris, O. Giet, E. Castermans, R. Greimers, I. Di Stefano, A. Gothot, and Y. Beguin
Despite Inhibition of Hematopoietic Progenitor Cell Growth In Vitro, the Tyrosine Kinase Inhibitor Imatinib Does Not Impair Engraftment of Human CD133+ Cells into NOD/SCID{beta}2mNull Mice
Stem Cells,
July 1, 2006;
24(7):
1814 - 1821.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Foudi, P. Jarrier, Y. Zhang, M. Wittner, J.-F. Geay, Y. Lecluse, T. Nagasawa, W. Vainchenker, and F. Louache
Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4-/- chimeric mice
Blood,
March 15, 2006;
107(6):
2243 - 2251.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rosu-Myles, E. Stewart, J. Trowbridge, C. Y. Ito, P. Zandstra, and M. Bhatia
A unique population of bone marrow cells migrates to skeletal muscle via hepatocyte growth factor/c-met axis
J. Cell Sci.,
October 1, 2005;
118(19):
4343 - 4352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Guo, G. Hangoc, H. Bian, L. M. Pelus, and H. E. Broxmeyer
SDF-1/CXCL12 Enhances Survival and Chemotaxis of Murine Embryonic Stem Cells and Production of Primitive and Definitive Hematopoietic Progenitor Cells
Stem Cells,
September 1, 2005;
23(9):
1324 - 1332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. J. Woo, T. J. Grand, M. F. Berry, P. Atluri, M. A. Moise, V. M. Hsu, J. Cohen, O. Fisher, J. Burdick, M. Taylor, et al.
Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy
J. Thorac. Cardiovasc. Surg.,
August 1, 2005;
130(2):
321 - 329.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Dalakas, P. N. Newsome, D. J. Harrison, and J. N. Plevris
Hematopoietic stem cell trafficking in liver injury
FASEB J,
August 1, 2005;
19(10):
1225 - 1231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Basu and H. E. Broxmeyer
Transforming growth factor-{beta}1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12
Blood,
July 15, 2005;
106(2):
485 - 493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Xu, E. Bruno, J. Chao, S. Huang, G. Finazzi, S. M. Fruchtman, U. Popat, J. T. Prchal, G. Barosi, R. Hoffman, et al.
Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases
Blood,
June 1, 2005;
105(11):
4508 - 4515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. E. Broxmeyer, C. M. Orschell, D. W. Clapp, G. Hangoc, S. Cooper, P. A. Plett, W. C. Liles, X. Li, B. Graham-Evans, T. B. Campbell, et al.
Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist
J. Exp. Med.,
April 18, 2005;
201(8):
1307 - 1318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Fukuda, H. E. Broxmeyer, and L. M. Pelus
Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1{alpha}(CXCL12)/CXCR4 axis
Blood,
April 15, 2005;
105(8):
3117 - 3126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-F. Geay, D. Buet, Y. Zhang, A. Foudi, P. Jarrier, M. Berthebaud, A. G. Turhan, W. Vainchenker, and F. Louache
p210BCR-ABL inhibits SDF-1 Chemotactic Response via Alteration of CXCR4 Signaling and Down-regulation of CXCR4 Expression
Cancer Res.,
April 1, 2005;
65(7):
2676 - 2683.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. B. Kwak, S. W. Lee, H. M. Jin, H. Ha, S. H. Lee, S. Takeshita, S. Tanaka, H.-M. Kim, H.-H. Kim, and Z. H. Lee
Monokine induced by interferon-{gamma} is induced by receptor activator of nuclear factor {kappa}B ligand and is involved in osteoclast adhesion and migration
Blood,
April 1, 2005;
105(7):
2963 - 2969.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Kryczek, A. Lange, P. Mottram, X. Alvarez, P. Cheng, M. Hogan, L. Moons, S. Wei, L. Zou, V. Machelon, et al.
CXCL12 and Vascular Endothelial Growth Factor Synergistically Induce Neoangiogenesis in Human Ovarian Cancers
Cancer Res.,
January 15, 2005;
65(2):
465 - 472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Okabe, S. Fukuda, Y.-J. Kim, M. Niki, L. M. Pelus, K. Ohyashiki, P. P. Pandolfi, and H. E. Broxmeyer
Stromal cell-derived factor-1{alpha}/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1
Blood,
January 15, 2005;
105(2):
474 - 480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Giebel, D. Corbeil, J. Beckmann, J. Hohn, D. Freund, K. Giesen, J. Fischer, G. Kogler, and P. Wernet
Segregation of lipid raft markers including CD133 in polarized human hematopoietic stem and progenitor cells
Blood,
October 15, 2004;
104(8):
2332 - 2338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Monfardini, V. Van Merris, M. Paape, L. Duchateau, and C. Burvenich
L-Selectin and Chemotaxis Throughout Bone Marrow Granulocyte Maturation in the Bovine
J Dairy Sci,
October 1, 2004;
87(10):
3350 - 3357.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Christopherson II, G. Hangoc, C. R. Mantel, and H. E. Broxmeyer
Modulation of Hematopoietic Stem Cell Homing and Engraftment by CD26
Science,
August 13, 2004;
305(5686):
1000 - 1003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. C. Rombouts, B. Pavic, B. Lowenberg, and R. E. Ploemacher
Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia
Blood,
July 15, 2004;
104(2):
550 - 557.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. T. Suratt, J. M. Petty, S. K. Young, K. C. Malcolm, J. G. Lieber, J. A. Nick, J.-A. Gonzalo, P. M. Henson, and G. S. Worthen
Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis
Blood,
July 15, 2004;
104(2):
565 - 571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kimura, A. M. Boehmler, G. Seitz, S. Kuci, T. Wiesner, V. Brinkmann, L. Kanz, and R. Mohle
The sphingosine 1-phosphate receptor agonist FTY720 supports CXCR4-dependent migration and bone marrow homing of human CD34+ progenitor cells
Blood,
June 15, 2004;
103(12):
4478 - 4486.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Evans, R. Tonge, D. Blinco, A. Pierce, J. Shaw, Y. Lu, H. G. Hamzah, A. Gray, C. P. Downes, S. J. Gaskell, et al.
Comparative proteomics of primitive hematopoietic cell populations reveals differences in expression of proteins regulating motility
Blood,
May 15, 2004;
103(10):
3751 - 3759.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ueda, K. Yang, S. J. Foster, M. Kondo, and G. Kelsoe
Inflammation Controls B Lymphopoiesis by Regulating Chemokine CXCL12 Expression
J. Exp. Med.,
January 5, 2004;
199(1):
47 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
A. G. Kayali, K. Van Gunst, I. L. Campbell, A. Stotland, M. Kritzik, G. Liu, M. Flodstrom-Tullberg, Y.-Q. Zhang, and N. Sarvetnick
The stromal cell-derived factor-1{alpha}/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas
J. Cell Biol.,
November 24, 2003;
163(4):
859 - 869.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Villalba, O. Salvucci, Y. Aoki, M. D. L. L. Sierra, G. Gupta, D. Davis, K. Wyvill, R. Little, R. Yarchoan, and G. Tosato
Serum inactivation contributes to the failure of stromal-derived factor-1 to block HIV-I infection in vivo
J. Leukoc. Biol.,
November 1, 2003;
74(5):
880 - 888.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. C. Liles, H. E. Broxmeyer, E. Rodger, B. Wood, K. Hubel, S. Cooper, G. Hangoc, G. J. Bridger, G. W. Henson, G. Calandra, et al.
Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist
Blood,
October 15, 2003;
102(8):
2728 - 2730.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Whetton, Y. Lu, A. Pierce, L. Carney, and E. Spooncer
Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1
Blood,
October 15, 2003;
102(8):
2798 - 2802.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Wright, T. L. de Lera, C. Garcia-Moruja, R. Lillo, F. Garcia-Sanchez, A. Caruz, and J. Teixido
Transforming growth factor-{beta}1 down-regulates expression of chemokine stromal cell-derived factor-1: functional consequences in cell migration and adhesion
Blood,
September 15, 2003;
102(6):
1978 - 1984.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. van Buul, C. Voermans, J. van Gelderen, E. C. Anthony, C. E. van der Schoot, and P. L. Hordijk
Leukocyte-Endothelium Interaction Promotes SDF-1-dependent Polarization of CXCR4
J. Biol. Chem.,
August 8, 2003;
278(32):
30302 - 30310.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Christopherson II, S. Cooper, and H. E. Broxmeyer
Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells
Blood,
June 15, 2003;
101(12):
4680 - 4686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
H. E. Broxmeyer, S. Cooper, L. Kohli, G. Hangoc, Y. Lee, C. Mantel, D. W. Clapp, and C. H. Kim
Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo
J. Immunol.,
January 1, 2003;
170(1):
421 - 429.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Cristillo, M. J. Macri, and B. E. Bierer
Differential chemokine expression profiles in human peripheral blood T lymphocytes: dependence on T-cell coreceptor and calcineurin signaling
Blood,
January 1, 2003;
101(1):
216 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Christopherson II, G. Hangoc, and H. E. Broxmeyer
Cell Surface Peptidase CD26/Dipeptidylpeptidase IV Regulates CXCL12/Stromal Cell-Derived Factor-1{alpha}-Mediated Chemotaxis of Human Cord Blood CD34+ Progenitor Cells
J. Immunol.,
December 15, 2002;
169(12):
7000 - 7008.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kijima, G. Maulik, P. C. Ma, E. V. Tibaldi, R. E. Turner, B. Rollins, M. Sattler, B. E. Johnson, and R. Salgia
Regulation of Cellular Proliferation, Cytoskeletal Function, and Signal Transduction through CXCR4 and c-Kit in Small Cell Lung Cancer Cells
Cancer Res.,
November 1, 2002;
62(21):
6304 - 6311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Askenasy and D. L. Farkas
Optical Imaging of PKH-Labeled Hematopoietic Cells in Recipient Bone Marrow In Vivo
Stem Cells,
November 1, 2002;
20(6):
501 - 513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Bug, T. Rossmanith, R. Henschler, L.A. Kunz-Schughart, B. Schroder, M. Kampfmann, M. Kreutz, D. Hoelzer, and O. G. Ottmann
Rho family small GTPases control migration of hematopoietic progenitor cells into multicellular spheroids of bone marrow stroma cells
J. Leukoc. Biol.,
October 1, 2002;
72(4):
837 - 845.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ptasznik, E. Urbanowska, S. Chinta, M. A. Costa, B. A. Katz, M. A. Stanislaus, G. Demir, D. Linnekin, Z. K. Pan, and A. M. Gewirtz
Crosstalk Between BCR/ABL Oncoprotein and CXCR4 Signaling through a Src Family Kinase in Human Leukemia Cells
J. Exp. Med.,
September 2, 2002;
196(5):
667 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Netelenbos, S. Zuijderduijn, J. van den Born, F. L. Kessler, S. Zweegman, P. C. Huijgens, and A. M. Drager
Proteoglycans guide SDF-1-induced migration of hematopoietic progenitor cells
J. Leukoc. Biol.,
August 1, 2002;
72(2):
353 - 362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Lee, A. Gotoh, H.-J. Kwon, M. You, L. Kohli, C. Mantel, S. Cooper, G. Hangoc, K. Miyazawa, K. Ohyashiki, et al.
Enhancement of intracellular signaling associated with hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in synergy with other cytokines
Blood,
May 29, 2002;
99(12):
4307 - 4317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. B. Mazo, E. J. Quackenbush, J. B. Lowe, and U. H. von Andrian
Total body irradiation causes profound changes in endothelial traffic molecules for hematopoietic progenitor cell recruitment to bone marrow
Blood,
May 13, 2002;
99(11):
4182 - 4191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ueda, M. Mizuki, H. Ikeda, T. Tsujimura, I. Matsumura, K. Nakano, H. Daino, Z.-i. Honda, J. Sonoyama, H. Shibayama, et al.
Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration
Blood,
May 1, 2002;
99(9):
3342 - 3349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Salvucci, L. Yao, S. Villalba, A. Sajewicz, S. Pittaluga, and G. Tosato
Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1
Blood,
April 15, 2002;
99(8):
2703 - 2711.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. CRISTILLO, H. C. HIGHBARGER, R. L. DEWAR, D. S. DIMITROV, H. GOLDING, and B. E. BIERER
Up-regulation of HIV coreceptor CXCR4 expression in human T lymphocytes is mediated in part by a cAMP-responsive element
FASEB J,
March 1, 2002;
16(3):
354 - 364.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-J. Lataillade, D. Clay, P. Bourin, F. Herodin, C. Dupuy, C. Jasmin, and M.-C. Le Bousse-Kerdiles
Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G0/G1 transition in CD34+ cells: evidence for an autocrine/paracrine mechanism
Blood,
February 15, 2002;
99(4):
1117 - 1129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. van Buul, C. Voermans, V. van den Berg, E. C. Anthony, F. P. J. Mul, S. van Wetering, C. E. van der Schoot, and P. L. Hordijk
Migration of Human Hematopoietic Progenitor Cells Across Bone Marrow Endothelium Is Regulated by Vascular Endothelial Cadherin
J. Immunol.,
January 15, 2002;
168(2):
588 - 596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
T. Jinquan, L. Anting, H. H. Jacobi, C. Glue, C. Jing, L. P. Ryder, H. O. Madsen, A. Svejgaard, P. S. Skov, H.-J. Malling, et al.
CXCR3 Expression on CD34+ Hemopoietic Progenitors Induced by Granulocyte-Macrophage Colony-Stimulating Factor: II. Signaling Pathways Involved
J. Immunol.,
October 15, 2001;
167(8):
4405 - 4413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Dubois, C. Massacrier, and C. Caux
Selective attraction of naive and memory B cells by dendritic cells
J. Leukoc. Biol.,
October 1, 2001;
70(4):
633 - 641.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hattori, B. Heissig, K. Tashiro, T. Honjo, M. Tateno, J.-H. Shieh, N. R. Hackett, M. S. Quitoriano, R. G. Crystal, S. Rafii, et al.
Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells
Blood,
June 1, 2001;
97(11):
3354 - 3360.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bautz, C. Denzlinger, L. Kanz, and R. Mohle
Chemotaxis and transendothelial migration of CD34+ hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1
Blood,
June 1, 2001;
97(11):
3433 - 3440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Nagata, M. Oda, H. Nakata, Y. Shozaki, T. Kozasa, and K. Todokoro
A novel regulator of G-protein signaling bearing GAP activity for G{alpha}i and G{alpha}q in megakaryocytes
Blood,
May 15, 2001;
97(10):
3051 - 3060.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Kollet, A. Spiegel, A. Peled, I. Petit, T. Byk, R. Hershkoviz, E. Guetta, G. Barkai, A. Nagler, and T. Lapidot
Rapid and efficient homing of human CD34+CD38{-}/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice
Blood,
May 15, 2001;
97(10):
3283 - 3291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Chan, S. J. Hyduk, and M. I. Cybulsky
Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte {alpha}4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest: An Early Step in the Process of Emigration
J. Exp. Med.,
May 14, 2001;
193(10):
1149 - 1158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. R. Fedyk, D. Jones, H. O. D. Critchley, R. P. Phipps, T. M. Blieden, and T. A. Springer
Expression of Stromal-Derived Factor-1 Is Decreased by IL-1 and TNF and in Dermal Wound Healing
J. Immunol.,
May 1, 2001;
166(9):
5749 - 5754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kapur, R. Cooper, L. Zhang, and D. A. Williams
Cross-talk between {alpha}4{beta}1/{alpha}5{beta}1 and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways
Blood,
April 1, 2001;
97(7):
1975 - 1981.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Voermans, M. L. K. Kooi, S. Rodenhuis, H. van der Lelie, C. E. van der Schoot, and W. R. Gerritsen
In vitro migratory capacity of CD34+ cells is related to hematopoietic recovery after autologous stem cell transplantation
Blood,
February 1, 2001;
97(3):
799 - 804.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Sanz-Rodriguez, A. Hidalgo, and J. Teixido
Chemokine stromal cell-derived factor-1{alpha} modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1
Blood,
January 15, 2001;
97(2):
346 - 351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Dorge, T. Neumann, M. Behrends, A. Skyschally, R. Schulz, C. Kasper, R. Erbel, and G. Heusch
Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation
Am J Physiol Heart Circ Physiol,
December 1, 2000;
279(6):
H2587 - H2592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yayoshi-Yamamoto, I. Taniuchi, and T. Watanabe
FRL, a Novel Formin-Related Protein, Binds to Rac and Regulates Cell Motility and Survival of Macrophages
Mol. Cell. Biol.,
September 15, 2000;
20(18):
6872 - 6881.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Brandes, D. F. Legler, B. Spoerri, P. Schaerli, and B. Moser
Activation-dependent modulation of B lymphocyte migration to chemokines
Int. Immunol.,
September 1, 2000;
12(9):
1285 - 1292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jinquan, S. Quan, H. H. Jacobi, C. Jing, A. Millner, B. Jensen, H. O. Madsen, L. P. Ryder, A. Svejgaard, H.-J. Malling, et al.
CXC chemokine receptor 3 expression on CD34+ hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma -inducible protein 10 and monokine induced by interferon gamma
Blood,
August 15, 2000;
96(4):
1230 - 1238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Yanai, N. Matsui, T. Furusawa, T. Okubo, and M. Obinata
Sphingosine-1-phosphate and lysophosphatidic acid trigger invasion of primitive hematopoietic cells into stromal cell layers
Blood,
July 1, 2000;
96(1):
139 - 144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tagaya, T. Kunisada, H. Yamazaki, T. Yamane, T. Tokuhisa, E. F. Wagner, T. Sudo, L. D. Shultz, and S.-I. Hayashi
Intramedullary and extramedullary B lymphopoiesis in osteopetrotic mice
Blood,
June 1, 2000;
95(11):
3363 - 3370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-F. Wang, I.-W. Park, and J. E. Groopman
Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C
Blood,
April 15, 2000;
95(8):
2505 - 2513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Majka, J. Ratajczak, B. Lee, M. Honczarenko, R. Douglas, M. A. Kowalska, L. Silberstein, A. M. Gewirtz, and M. Z. Ratajczak
The Role of HIV-Related Chemokine Receptors and Chemokines in Human Erythropoiesis in Vitro
Stem Cells,
March 1, 2000;
18(2):
128 - 138.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J.-J. Lataillade, D. Clay, C. Dupuy, S. Rigal, C. Jasmin, P. Bourin, and M.-C. L. Bousse-Kerdiles
Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival
Blood,
February 1, 2000;
95(3):
756 - 768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hodohara, N. Fujii, N. Yamamoto, and K. Kaushansky
Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK)
Blood,
February 1, 2000;
95(3):
769 - 775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.-S. Charbonnier, N. Kohrgruber, E. Kriehuber, G. Stingl, A. Rot, and D. Maurer
Macrophage Inflammatory Protein 3{alpha} Is Involved in the Constitutive Trafficking of Epidermal Langerhans Cells
J. Exp. Med.,
December 20, 1999;
190(12):
1755 - 1768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Naiyer, D.-Y. Jo, J. Ahn, R. Mohle, M. Peichev, G. Lam, R. L. Silverstein, M. A.S. Moore, and S. Rafii
Stromal Derived Factor-1-Induced Chemokinesis of Cord Blood CD34+ Cells (Long-Term Culture-Initiating Cells) Through Endothelial Cells Is Mediated by E-Selectin
Blood,
December 15, 1999;
94(12):
4011 - 4019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Salgia, E. Quackenbush, J. Lin, N. Souchkova, M. Sattler, D. S. Ewaniuk, K. M. Klucher, G. Q. Daley, S. K. Kraeft, R. Sackstein, et al.
The BCR/ABL Oncogene Alters the Chemotactic Response to Stromal-Derived Factor-1alpha
Blood,
December 15, 1999;
94(12):
4233 - 4246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Honczarenko, R. S. Douglas, C. Mathias, B. Lee, M. Z. Ratajczak, and L. E. Silberstein
SDF-1 Responsiveness Does Not Correlate With CXCR4 Expression Levels of Developing Human Bone Marrow B Cells
Blood,
November 1, 1999;
94(9):
2990 - 2998.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ishii, M. Nishihara, F. Ma, Y. Ebihara, K. Tsuji, S. Asano, T. Nakahata, and T. Maekawa
Expression of Stromal Cell-Derived Factor-1/Pre-B Cell Growth-Stimulating Factor Receptor, CXC Chemokine Receptor 4, on CD34+ Human Bone Marrow Cells Is a Phenotypic Alteration for Committed Lymphoid Progenitors
J. Immunol.,
October 1, 1999;
163(7):
3612 - 3620.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Tordjman, N. Ortega, L. Coulombel, J. Plouet, P.-H. Romeo, and V. Lemarchandel
Neuropilin-1 Is Expressed on Bone Marrow Stromal Cells: A Novel Interaction With Hematopoietic Cells?
Blood,
October 1, 1999;
94(7):
2301 - 2309.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. C. Broudy, N. L. Lin, W. C. Liles, S. J. Corey, B. O'Laughlin, S. Mou, and D. Linnekin
Signaling via Src Family Kinases Is Required for Normal Internalization of the Receptor c-Kit
Blood,
September 15, 1999;
94(6):
1979 - 1986.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Kim, C.-K. Qu, G. Hangoc, S. Cooper, N. Anzai, G.-S. Feng, and H. E. Broxmeyer
Abnormal Chemokine-induced Responses of Immature and Mature Hematopoietic Cells from Motheaten Mice Implicate the Protein Tyrosine Phosphatase SHP-1 in Chemokine Responses
J. Exp. Med.,
September 6, 1999;
190(5):
681 - 690.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kinoshita, T. Sekiguchi, M.-j. Xu, Y. Ito, A. Kamiya, K.-i. Tsuji, T. Nakahata, and A. Miyajima
Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis
PNAS,
June 22, 1999;
96(13):
7265 - 7270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kawabata, M. Ujikawa, T. Egawa, H. Kawamoto, K. Tachibana, H. Iizasa, Y. Katsura, T. Kishimoto, and T. Nagasawa
A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution
PNAS,
May 11, 1999;
96(10):
5663 - 5667.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Dürig, N. G. Testa, and C. M. Heyworth
Distinct Biological Effects of Macrophage Inflammatory Protein-1{alpha} and Stroma-Derived Factor-1{alpha} on CD34+ Hemopoietic Cells
Stem Cells,
March 1, 1999;
17(2):
62 - 71.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Reid, A. Ritchie, L. Boring, J. Gosling, S. Cooper, G. Hangoc, I. F. Charo, and H. E. Broxmeyer
Enhanced Myeloid Progenitor Cell Cycling and Apoptosis in Mice Lacking the Chemokine Receptor, CCR2
Blood,
March 1, 1999;
93(5):
1524 - 1533.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Peled, I. Petit, O. Kollet, M. Magid, T. Ponomaryov, T. Byk, A. Nagler, H. Ben-Hur, A. Many, L. Shultz, et al.
Dependence of Human Stem Cell Engraftment and Repopulation of NOD/SCID Mice on CXCR4
Science,
February 5, 1999;
283(5403):
845 - 848.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. W. Cole, B. D. Jamieson, and J. A. Zack
cAMP Up-Regulates Cell Surface Expression of Lymphocyte CXCR4: Implications for Chemotaxis and HIV-1 Infection
J. Immunol.,
February 1, 1999;
162(3):
1392 - 1400.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Parichy, J. Rawls, S. Pratt, T. Whitfield, and S. Johnson
Zebrafish sparse corresponds to an orthologue of c-kit and is required for the morphogenesis of a subpopulation of melanocytes, but is not essential for hematopoiesis or primordial germ cell development
Development,
January 8, 1999;
126(15):
3425 - 3436.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. Dutt, J.-F. Wang, and J. E. Groopman
Stromal Cell-Derived Factor-1{alpha} and Stem Cell Factor/kit Ligand Share Signaling Pathways in Hemopoietic Progenitors: A Potential Mechanism for Cooperative Induction of Chemotaxis
J. Immunol.,
October 1, 1998;
161(7):
3652 - 3658.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Kim, L. M. Pelus, J. R. White, and H. E. Broxmeyer
Macrophage-Inflammatory Protein-3{beta}/EBI1-Ligand Chemokine/CK{beta}-11, a CC Chemokine, Is a Chemoattractant with a Specificity for Macrophage Progenitors Among Myeloid Progenitor Cells
J. Immunol.,
September 1, 1998;
161(5):
2580 - 2585.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hamada, R. Mohle, J. Hesselgesser, J. Hoxie, R. L. Nachman, M. A.S. Moore, and S. Rafii
Transendothelial Migration of Megakaryocytes in Response to Stromal Cell-derived Factor 1 (SDF-1) Enhances Platelet Formation
J. Exp. Med.,
August 3, 1998;
188(3):
539 - 548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-F. Wang, Z.-Y. Liu, and J. E. Groopman
The alpha -Chemokine Receptor CXCR4 Is Expressed on the Megakaryocytic Lineage From Progenitor to Platelets and Modulates Migration and Adhesion
Blood,
August 1, 1998;
92(3):
756 - 764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract
