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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 107-112
Murine Hematopoietic Progenitor Cells With Colony-Forming or
Radioprotective Capacity Lack Expression of the
 2-Integrin LFA-1
By
Johannes F.M. Pruijt,
Yvette van Kooyk,
Carl G. Figdor,
Roel Willemze, and
Willem E. Fibbe
From the Laboratory of Experimental Hematology, Department of
Hematology, Leiden University Medical Center, Leiden; and the
Department of Tumor Immunology, University Hospital Nijmegen, Nijmegen,
The Netherlands.
 |
ABSTRACT |
Recently, we have demonstrated that antibodies that block the
function of the  2-integrin leukocyte function-associated
antigen-1 (LFA-1) completely abrogate the rapid mobilization of
hematopoietic progenitor cells (HPC) with colony-forming and
radioprotective capacity induced by interleukin-8 (IL-8) in mice. These
findings suggested a direct inhibitory effect of these antibodies on
LFA-1-mediated transmigration of stem cells through the bone marrow
endothelium. Therefore, we studied the expression and functional role
of LFA-1 on murine HPC in vitro and in vivo. In steady state bone
marrow ± 50% of the mononuclear cells (MNC) were
LFA-1neg. Cultures of sorted cells, supplemented with
granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage
colony-stimulating factor (GM-CSF)/IL-1/IL-3/IL-6/stem cell factor
(SCF) and erythropoietin (EPO) indicated that the
LFA-1neg fraction contained the majority of the
colony-forming cells (CFCs) (LFA-1neg 183 ± 62/7,500 cells v LFA-1pos 29 ± 17/7,500 cells,
P < .001). We found that the radioprotective capacity resided
almost exclusively in the LFA-1neg cell fraction, the
radioprotection rate after transplantation of 103, 3 × 103, 104, and 3 × 104 cells being
63%, 90%, 100%, and 100% respectively. Hardly any radioprotection
was obtained from LFA-1pos cells. Similarly, in cytokine
(IL-8 and G-CSF)-mobilized blood, the LFA-1neg fraction,
which comprised 5% to 10% of the MNC, contained the majority of the
colony-forming cells, as well as almost all cells with radioprotective
capacity. Subsequently, primitive bone marrow-derived HPC, represented
by Wheat-germ-agglutinin (WGA)+/Lineage
(Lin) /Rhodamine (Rho) sorted cells, were
examined. More than 95% of the Rho cells were
LFA-1neg. Cultures of sorted cells showed that the
LFA-1neg fraction contained all CFU. Transplantation of 150 Rho LFA-1neg or up to 600 RhoLFA-1pos cells protected 100% and 0% of
lethally irradiated recipient mice, respectively. These results show
that primitive murine HPC in steady-state bone marrow and of
cytokine-mobilized blood do not express LFA-1.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE PROLIFERATION and differentiation of
hematopoietic progenitor cells (HPC) is highly dependent on
interactions with components of the bone marrow microenvironment.
Adhesion molecules have been implicated to play a key role in this
complex network.1 Among these, 1- and
2-integrins are involved in the cellular interactions
between HPC, stromal cells, and the extracellular matrix
(ECM).2 A number of studies has indicated the expression of
the 1-integrins very late antigen (VLA)-4
(CD49d) and VLA-5 (CD49e) on colony-forming HPC.3-8
Leukocyte function-associated antigen  1 (LFA-1) (CD11a) has been
reported to be expressed on human committed progenitor cells and also
on a subset of more immature cells in vitro.2,9-13 In
long-term bone marrow cultures (LTBMC), the CD34+
LFA-1neg fraction generated more colony-forming cells
(CFCs) than LFA-1pos cells, indicating that
CD34+ LFA-1neg cells are more primitive than
CD34+ LFA-1pos cells.11 LFA-1 also
plays a role in the attachment of CD34+ cells to stromal
cells via one of its ligands, intercellular adhesion molecule
(ICAM)-12. In addition, it has been reported
that CD34+ LFA-1neg cells express LFA-1 within
24 hours of culture, without losing their growth
capacity.13 These results could explain the inhibition of
anti-LFA-1 antibodies on the generation of CFCs by CD34+
cells in stromal layers.11
Although these human studies have demonstrated that the in vitro
expression of LFA-1 is confined to the more mature HPC, no such studies
are reported on murine HPC. Recently, we have demonstrated that
anti-LFA-1 blocking antibodies completely prevent the interleukin-8 (IL-8)-induced mobilization of HPC with colony-forming or
radioprotective capacity in mice, without interfering with stem cell
homing.14 These experiments showed the direct involvement
of the 2-integrin LFA-1 in cytokine-induced
mobilization. From these studies, however, it remained unclear whether
LFA-1 expression on progenitor cells or on accessory cells was
responsible for this activity.
In the present report, we studied the expression and functional role of
LFA-1 on murine HPC in vitro and in vivo. We found that the
LFA-1neg fraction of BM-derived, as well as
cytokine-mobilized, blood mononuclear cells (MNC) contain the majority
of the CFCs and of cells with radioprotective capacity. Thus, murine
HPC with colony-forming or radioprotective capacity do not express
LFA-1.
| |
MATERIALS AND METHODS |
Mice.
BALB/c mice, with an age ranging between 8 to 12 weeks, were purchased
from Broekman BV, Someren, The Netherlands. Male donor animals were fed
commercial rodent chow and acidified water ad libitum. Recipient female
animals were maintained in a pathogen-free environment and fed water
containing ciprofloxacin 1 mg/mL (Bayer Nederland BV, Mijdrecht, The
Netherlands), polymyxin-B 70 µg/mL and saccharose 2 g/100 mL.
Preparation of cell suspensions.
Mice were killed by CO2 asphyxiation. Blood was obtained by
intracardiac puncture. Bone marrow cells were obtained by flushing the
femur under sterile conditions with RPMI 1640 containing 500 µg/mL
penicillin, 250 µg/mL streptomycin, and 2% fetal bovine serum (FBS;
GIBCO, Grand Island, NY). Cell counts were performed on a Sysmex F800
(TOA Medical Electronics Co, LTD, Kobe, Japan). Manual neutrophil
counts were performed after May Grünwald-Giemsa staining. Blood
and bone marrow-derived MNC suspensions were obtained by Ficoll
separation as described earlier.15
Stem cell purification.
Bone marrow and peripheral blood cells were separated by density
gradient centrifugation (Ficoll Isopaque; specific density [SD] 1.077g/cm3) at 4°C. Low-density
cells were labeled with the monoclonal rat-antimouse antibody H154.163
(anti-CD11a, IgG2a, directed against the adhesion molecule LFA-1,
kindly provided by Dr M. Pierres, Centre D' Immunologie De
Marseille-Luminy, Marseille, France16). Cells
were washed once and labeled with phycoerythrin
(PE)-conjugated goat antirat-IgG (GaRa-Pe) (Caltag, San
Francisco, CA). In some experiments, further purification of bone
marrow-derived low-density cells was performed as described
earlier.17 In short, low-density cells were labeled with a
biotin-conjugated myelomonocytic monoclonal antibody (LY-6C), and
PE-conjugated CD3e and CD45R/B220 (Pharmingen, San Diego, CA). After
washing once, the cells were further labeled with Streptavidin-Pe (Becton Dickinson, San José, CA) and fluorescein-conjugated
wheat-germ-agglutinin (WGA, 0.2 µg/mL, Vector, Burlingame, CA).
WGA+/Lin cells (±5%) were
fluorescence-activated cell sorted (FACS) using a FACSTAR cytometer
(Becton Dickinson) tuned at 488 nm. Sorted cells were stained with
rhodamine 123 (Rho; Molecular Probes Inc, Eugene, OR) at a
concentration of 0.1 µg/mL for 20 minutes at 37°C. Cells were
washed twice and incubated in medium without Rho for 20 minutes at 37°C. The Rho fraction
was sorted using the FACSTAR tuned at 514 nm. Sorted cells were used
for colony cultures or transplantation within 8 hours after killing the
donor mice.
Cytokines.
Recombinant human IL-8 was purified from Escherichia coli
expressing a synthetic gene18 and kindly provided by Dr
I.J.D. Lindley of the Novartis Forschungsinstitut, Vienna, Austria.
IL-8 had no colony-stimulating activity as reported
previously.19 The concentration of endotoxin was less than
0.05 EU/mL as determined by the Limulus amoebocyte lysate assay.
Recombinant granulocyte colony-stimulating factor (G-CSF) was purchased
from Amgen, Thousand Oaks, CA. For in vivo experiments, all agents were
diluted to the desired concentration in endotoxin-free
phosphate-buffered saline (PBS) containing 0.1% bovine serum albumin
(BSA) and administered as an intraperitoneal (IP) injection.
Progenitor cell assays.
To determine the clonogenic capacity of cells from purified cell
fractions, 7,500 sorted cells were cultured in 35 mm tissue culture
dishes in Iscove's modified Dulbecco's medium (IMDM), containing 30%
FBS, 1.1% methylcellulose 2 × 105
-mercaptoethanol, human transferrin (0.47 g/L) saturated with FeCl3.H2O in the presence of various growth
factors. Growth factors used included recombinant human (rhu) IL-1,
10 ng/mL (kindly provided by Hoffman-La Roche, Nutley, NJ); recombinant
murine (rmu) IL-3, 25 ng/mL (kindly provided by Novartis, Basel,
Switzerland); rhu-IL-6, 10 ng/mL (kindly provided by Dr L. Aarden, CLB,
Amsterdam, The Netherlands); rhu-G-CSF, 10 ng/mL (Amgen);
rmu-granulocyte-macrophage colony-stimulating factor (GM-CSF) 10 ng/mL
(kindly provided by Dr E. Liehl, Novartis Forschungsinstitut, Vienna,
Austria); rhu-stem cell factor (SCF), 25 ng/mL (kindly provided by
Amgen); and rhu-erythropoietin (EPO), 2 U/mL (Organon Technica N.V.,
Turnhout, Belgium). Colony-forming unit-granulocyte macrophage (CFU-GM)
were cultured as described previously.15 Briefly,
peripheral blood MNC were cultured in 3.5 cm dishes containing 5 × 105 cells per mL in semisolid medium in the
presence of murine GM-CSF (1.25 ng/mL). After 6 or 7 days of culture in
a fully humidified atmosphere of 37°C containing 5%
CO2, the number of colonies was scored using an inverted
microscope. Colonies were defined as aggregates of at least 20 cells.
Experimental design.
Mobilization of HPC by IL-8 was induced by a single IP injection of 30 µg of IL-8.20 After 20 minutes, the mice were killed by
CO2 asphyxiation and peripheral blood was obtained by
cardiac puncture. Mobilization by G-CSF was induced by IP
administration of 5 µg G-CSF once daily for 3 days. At day 4, the
animals were killed and blood was obtained as described. In
transplantation experiments, recipient mice were placed in a
polymethylmetaacetate (PMMA) box and given total body irradiation (8.75 Gy, Philips SL 75-5/6 mV linear accelerator; Philips Medical Systems,
Best, The Netherlands), divided in two parts in posterior-anterior and anterior-posterior position, at a dose rate of 4 Gy/min.
Decreasing cell numbers of sorted bone marrow or mobilized blood cells
were injected in the tail vein of lethally irradiated recipients. In each experiment, groups of 10 mice for each cell dose and cell fraction
were transplanted. The experimental protocol was approved by the
institutional ethical committee on animal experiments.
Late phase of engraftment.
Long-term repopulating ability (LTRA) of bone marrow-derived, as well
as cytokine-mobilized, blood LFA-1neg cells was assessed by
long-term bone marrow function, ie, the level of circulating mature
blood cells. Furthermore, the percentage of male cells was determined
in blood using fluorescence in situ hybridization with the
Y-chromosome-specific probe M34 as previously described.17
To assess multilineage engraftment, blood-derived granulocytes, T
lymphocytes, and B lymphocytes were sorted from individual
mice.21 Of each cell fraction, 200 nuclei were scored using
a Leitz Diaplan microscope (Leica, Wetzlar, Germany).
Statistical analysis.
Differences were evaluated using the Student's t-test.
P values of < .05 were considered statistically significant.
| |
RESULTS |
Expression of LFA-1 on steady-state bone marrow-derived cells and
cytokine-mobilized blood cells.
Staining of low-density steady-state bone marrow cells (8% to 15%)
with anti-LFA-1 antibodies showed that 40% to 60% was
LFA-1neg, whereas in G-CSF-, as well as IL-8-mobilized
blood, only 5% to 10% (Fig 1) and in
steady-state peripheral blood < 5% of the MNC were
LFA-1neg (data not shown).
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| Fig 1.
LFA-1 fluorescence histograms of steady state bone marrow
(A) or cytokine (G-CSF and IL-8)-mobilized blood MNC (B). The
LFA-1neg cell fraction comprised 40% to 60% and 5% to
10% of appropriately gated MNC from bone marrow and blood,
respectively.
|
|
Colony-forming capacity of LFA-1 sorted bone marrow and
cytokine-mobilized blood cells.
After sorting, we determined the clonogenic capacity of bone
marrow-derived LFA-1neg and LFA-1pos cells in
medium containing a cocktail of growth factors (G-CSF, GM-CSF, IL-1,
IL-3, IL-6, SCF, and EPO). Figure 2 shows
that the majority of the CFCs resided in the LFA-1neg
fraction (LFA-1neg 183 ± 62, n = 10 v
LFA-1pos 29 ± 17 CFU per 7,500 sorted cells; mean ± standard deviation [SD], n = 6, P < .001). Similar results
were obtained with cytokine-mobilized blood cells
(Fig 3). Although the frequency of CFCs was
lower in all fractions, colonies were also predominantly found in the LFA-1neg fraction (LFA-1neg 28.5 ± 18 v LFA-1pos 2 ± 1.5 CFU/7,500 sorted
cells for G-CSF; mean ± SD, n = 5, P < .05 and
LFA-1neg 7.5 ± 3 v LFA-1pos 1.5 ± 1 CFU/7,500 sorted cells for IL-8, respectively; mean ± SD, n = 7, P < .01, Fig 3).
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| Fig 2.
Number of colonies formed by 7,500 sorted LFA-1 negative
(LFA-1), positive (LFA-1+), or total
(LFA-1tot) bone marrow MNC. Results are expressed as mean ± SD. *P < .001.
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| Fig 3.
Number of colonies formed by 7,500 sorted
LFA-1, LFA-1+, or LFA-1tot
cytokine-mobilized blood MNC. Mice were treated with daily IP
injections of 5 µg G-CSF for 3 days or with a single IP injection of
30 µg IL-8. Results are expressed as mean ± SD. *P < .05 and **P < .01.
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Radioprotective capacity of LFA-1 sorted bone marrow cells.
To assess the radioprotective capacity of the LFA-1neg and
LFA-1pos cell fractions, lethally irradiated recipient mice
were transplanted with increasing numbers of LFA-1neg and
LFA-1pos sorted bone marrow-derived MNC. The
radioprotective capacity resided almost entirely in the
LFA-1neg cell fraction, as radioprotection after
transplantation of 103, 3 × 103,
104, and 3 × 104
LFA-1neg cells resulted in 63%, 90%, 100%, and 100%
survival, respectively (Fig 4). In
contrast, after transplantation of 3 × 103,
104, and 3 × 104 LFA-1pos
cells, a radioprotection rate of 5%, 5%, and 15% was obtained (Fig
4).
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| Fig 4.
Survival of lethally irradiated (8.75 Gy) recipient mice
for at least 4 weeks after transplantation of increasing numbers of
LFA-1neg and LFA-1pos sorted bone marrow MNC.
Survival data are expressed as absolute percentages of two experiments
with 10 mice transplanted per group in each experiment.
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Radioprotective capacity of cytokine-mobilized LFA-1 sorted blood
cells.
To study the radioprotective capacity of the mobilized LFA-1 sorted
MNC, recipient mice were lethally irradiated and transplanted with a
fixed number of LFA-1 sorted cells. Because the majority of CFCs was
confined to the LFA-1neg cell fraction, cell doses of
LFA-1neg and LFA-1pos cell fractions were
chosen in relation to their relative frequency and to the total number
of MNC required for radioprotection (1.5 × 105 for
G-CSF- and 5 × 105 for IL-8-mobilized
cells).20,22 Because after mobilization with G-CSF the
LFA-1neg fraction comprised 8.5% of the MNC, 8.5% of 1.5 × 105 (12,750) LFA-1neg cells were
transplanted and 1.5 × 105 LFA-1pos
cells. The survival rate of animals transplanted with
LFA-1neg cells was similar to animals transplanted with the
LFA-1 unsorted fraction (60% for total MNC and 70% for the
LFA-1neg fraction). No animals survived in the group
transplanted with LFA-1pos cells (n = 10 mice per group,
Fig 5). After mobilization with IL-8, the
LFA-1neg fraction comprised 5% of the MNC, resulting in
transplantation of 5 × 105 LFA-1pos cells
and 25,000 LFA-1neg cells (5% of 5 × 105). The survival rate of recipient mice transplanted with
IL-8-mobilized LFA-1neg MNC was 60%. A 50% survival rate
was observed after transplantation of 5 × 105
LFA-1pos MNC (n = 10 mice per group, Fig 5).
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| Fig 5.
Survival data of lethally irradiated (8.75 Gy) recipient
mice for at least 4 weeks after transplantation of LFA-1 sorted
cytokine-mobilized blood cells. Donor mice were pretreated with daily
IP injections of 5 µg G-CSF for 3 days or a single IP injection of 30 µg IL-8. With G-CSF, a total number of 1.5 × 105 MNC
(LFA-1tot), 1.5 × 105 LFA-1pos,
and 12,750 LFA-1neg cells were transplanted and with IL-8,
a total number of 5 × 105 LFA-1pos and 25,000 LFA-1neg cells were transplanted. Survival data are
expressed as percentages of 10 mice transplanted per group in one
experiment.
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LTRA of bone marrow-derived and cytokine-mobilized blood-derived
LFA-1neg cells.
In addition to radioprotection or short-term repopulating ability
(STRA), also LTRA was assessed by long-term bone marrow function of
bone marrow-derived, as well as G-CSF- and IL-8-mobilized LFA-1neg cells (Table 1). The
time interval after transplantation between the three groups varied,
ie, 8 months for BM recipients, 7 months for IL-8, and 5 months for
recipients transplanted with G-CSF-mobilized cells. To exclude
lineage-specific chimerism, three mice from each group were killed and
blood was obtained by cardiac puncture. Granulocytes, B lymphocytes,
and T lymphocytes were sorted from individual mice. The mean percentage
of male cells for the three lineages was 99%, 98%, and 84% for BM,
76%, 91%, and 76% for IL-8, and 75%, 73%, and 59% for
G-CSF-transplanted recipient mice, showing that chimerism was
multilineage.
Expression and function of LFA-1 on primitive HPC.
Because LFA-1 is expressed on all leukocytes,23
LFA-1pos MNC will contain mainly lymphocytes, monocytes,
and mature committed progenitor cells. We therefore studied the
expression and functional role of LFA-1 on primitive HPC with
repopulating ability, represented by bone marrow-derived
WGA+/Lin/Rho
cells.17 More than 95% of the sorted cells were
LFA-1neg. Cultures of 750 sorted cells showed that the
LFA-1neg fraction contained all CFU with a high plating
efficiency of ± 33% (247 v 1, mean, n = 4 experiments).
Transplantation of 150 Rho LFA-1neg or
up to 600 Rho LFA-1pos cells protected
100% and 0% of lethally irradiated recipient mice, respectively (n = 10 mice per group in one experiment).
| |
DISCUSSION |
A number of studies has indicated the variable expression of LFA-1 on
human CD34+ cells in steady state bone marrow, as well as
cytokine-mobilized, blood.13,24-28 In addition, several
reports have demonstrated that the in vitro expression of LFA-1 is
confined to the more mature HPC.9,11,13 However, no such
studies are reported on murine HPC. Therefore, we first examined the
expression of LFA-1 on bone marrow-derived and cytokine-mobilized MNC.
In accordance with Miller et al,29 approximately 40% to
50% of murine bone marrow MNC were LFA-1neg. In
cytokine-mobilized blood, 5% to 10% of IL-8- as well as
G-CSF-mobilized, blood MNC were LFA-1neg. Virtually no
expression of LFA-1 was found on primitive HPC. The differences in
LFA-1 expression between cytokine-mobilized peripheral blood (90% to
95%), steady-state bone marrow (50% to 60%), and primitive HPC
(<5%) coincides with the expected number of mature leukocytes in
these fractions, which all express LFA-123 and is reflected
in the different plating efficiencies of sorted LFA-1neg
cells from these fractions (cytokine-mobilized blood 0.1% to 0.4%,
bone marrow 2.4%, and primitive HPC 33%).
Several studies report the induction of LFA-1 on primitive
LFA-1neg bone marrow cells during in vitro culture in
humans13 and mice.30 The acquisition of LFA-1
did not preclude the multilineage colony-forming potential of these
cells.13 In contrast, the growth potential of
CD34+LFA-1pos sorted BM cells was much less and
consisted of small macrophage-like colonies.13 Therefore,
it was postulated for human HPC that LFA-1 is expressed by default,
providing maturing bone marrow cells with adhesion molecules enabling
migration into the peripheral blood. Our data do not support the active
downregulation of LFA-1 on HPC in the bone marrow microenvironment, as
in cytokine-mobilized blood, both colony formation and radioprotective
capacity were confined to the LFA-1neg cell fraction,
indicating that in vivo circulating stem cells do not acquire LFA-1
after mobilization.
The possibility was considered that the results of transplantation
experiments with mobilized blood were determined by the absolute
numbers of repopulating cells present in the LFA-1neg and
positive cell fractions, ie, it was conceivable that the absolute
number of repopulating cells in the LFA-1pos fraction was
equal or even higher than in the LFA-1neg fraction. Cell
doses of the LFA-1neg and LFA-1pos fractions
were therefore chosen in relation to the total number of MNC required
for radioprotection.20,22 A number of 150,000 G-CSF-mobilized MNC resulted in 60% radioprotection. An equal number
of LFA-1pos cells did not mediate radioprotection, whereas
transplantation of 12,750 LFA-1neg cells resulted in 70%
survival. From these data, we concluded that the cells responsible for
radioprotection after transplantation of unpurified blood resided
completely in the LFA-1neg cell fraction.
In conclusion, we showed that the majority of murine bone marrow- and
cytokine-mobilized blood-derived CFCs, cells with radioprotective capacity, and primitive HPC do not express LFA-1. In accordance with
these results, a recent report defines the phenotype of a Sca+/Lin engrafting murine progenitor
cell as LFA-1neg.31 Our data are compatible
with human in vivo studies, as patients with the leukocyte adhesion
deficiency syndrome (LAD), characterized by mutations in the integrin
2 chain, lack defects in early
hematopoiesis.32 Furthermore, treatment with anti-LFA-1
antibodies as part of the conditioning regimen for allogeneic bone
marrow transplantation in immunodeficient children improved
engraftment.33,34 As stem cells appear not to express
LFA-1, whereas almost all leukemias do,35 negative
selection for LFA-1 could be a useful addition in purging of autologous
bone marrrow transplants.36
Recently, we reported that anti-LFA-1 blocking antibodies completely
prevent the rapid IL-8-induced mobilization of HPC,14 suggesting a direct effect of the antibody on LFA-1 expressed on HPC.
However, our results clearly show that HPC with both colony-forming and
radioprotective capacity does not express LFA-1 and therefore these
cells are unable to function as direct targets for the blocking antibody. These data seem to indicate that an accessory cell, expressing LFA-1, as well as IL-8 receptors, plays an important role in
IL-8-induced mobilization. IL-8 is a potent inducer of the release of
matrix metalloproteinases as gelatinase B (MMP-9) by
neutrophils.37 Furthermore, preliminary experiments in
monkeys have indicated the rapid induction of MMP-9 by IL-8 and
neutralizing antibodies directed against MMP-9 block the IL-8-induced
mobilization of HPC.38 Taken together, our data support the
hypothesis that neutrophils, expressing LFA-1, may serve as
intermediate cells in the induction of mobilization. In accordance with
this hypothesis, Liu et al39 have found severely impaired
IL-8-induced mobilization in G-CSF receptor-deficient mice. Further
studies are underway to study the possible role of neutrophils and
metalloproteinases as key regulators in IL-8-induced stem cell
mobilization.
| |
ACKNOWLEDGMENT |
The authors thank Maarten van der Keur and Arie van der Marel for their
technical assistance in the cell sorting experiments, Peter de Jong for
his excellent animal care, Karin Kleiverda for performing the in situ
hybridizations, and Sandra van Vliet for purifying the LFA-1
antibodies.
| |
FOOTNOTES |
Submitted June 22, 1998;
accepted August 28, 1998.
Supported by the Dutch Cancer Society (NKB) Grant No. RUL 95-1091.
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.
Address reprint requests to Johannes F.M. Pruijt, MD, Department of
Hematology, Leiden University Medical Center, Bldg 1, C2-R, PO Box
9600, 2300 RC Leiden, The Netherlands.
| |
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Abstract
Introduction