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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3289-3296
CHEMOKINES
The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and
VLA-5 on immature human CD34+ cells: role in
transendothelial/stromal migration and engraftment of NOD/SCID mice
Amnon Peled,
Orit Kollet,
Tanya Ponomaryov,
Isabelle Petit,
Suzanna Franitza,
Valentin Grabovsky,
Michal Magid Slav,
Arnon Nagler,
Ofer Lider,
Ronen Alon,
Dov Zipori, and
Tsvee Lapidot
From the Departments of Immunology and Molecular Cell Biology, The
Weizmann Institute of Science, Rehovot, Israel, and the Haddasa
University Hospital, Jerusalem, Israel.
 |
Abstract |
Hematopoietic stem cell homing and engraftment require several
adhesion interactions, which are not fully understood. Engraftment of
nonobese/severe combined immunodeficiency (NOD/SCID) mice by human stem
cells is dependent on the major integrins very late activation
antigen-4 (VLA-4); VLA-5; and to a lesser degree, lymphocyte function
associated antigen-1 (LFA-1). Treatment of human CD34+
cells with antibodies to either VLA-4 or VLA-5 prevented engraftment, and treatment with anti-LFA-1 antibodies significantly reduced the
levels of engraftment. Activation of CD34+ cells, which
bear the chemokine receptor CXCR4, with stromal derived factor 1 (SDF-1) led to firm adhesion and transendothelial migration, which was
dependent on LFA-1/ICAM-1 (intracellular adhesion molecule-1) and
VLA-4/VCAM-1 (vascular adhesion molecule-1). Furthermore,
SDF-1-induced polarization and extravasation of
CD34+/CXCR4+ cells through the
extracellular matrix underlining the endothelium was dependent on
both VLA-4 and VLA-5. Our results demonstrate that repopulating
human stem cells functionally express LFA-1, VLA-4, and VLA-5.
Furthermore, this study implies a novel approach to further advance
clinical transplantation.
(Blood. 2000;95:3289-3296)
© 2000 by The American Society of Hematology.
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Introduction |
During development, hematopoietic stem cells migrate
from the yolk sac and the aorta gonad mesonephros (AGM) region into the fetal liver and then into the fetal bone marrow. Stem cells
continuously produce all mature blood cells and are defined in
functional repopulation assays based on their ability to home to the
bone marrow microenvironment and to durably repopulate transplanted
recipients with myeloid and lymphoid cells.1-4 We and
others developed functional in vivo assays for primitive human SCID
(severe combined immunodeficiency) repopulating cells (SRCs), which
provide a means to measure the multilineage engraftment properties of
human stem cells.5-7 Determining the role of chemokines and
adhesion molecules in human stem cell migration and engraftment will
help to identify the mechanisms that govern stem cell development and
advance clinical stem cell transplantation.
Recently we discovered that human stem cell engraftment of nonobese
(NOD)/SCID mice is dependent on the expression of the chemokine SDF-1
and its receptor CXCR4.8 However, the possible role of
SDF-1 in mediating activation of different adhesion molecules, which
are expressed on repopulating human stem cells during this process, is
currently unknown. Stem cell homing and engraftment is presumably a
multistep process that shares some common features with the migration
of leukocytes to inflammatory sites and homing of lymphocytes into
lymph nodes.9-11 First, the transplanted human cells, which
migrate through the blood circulation, must interact with the bone
marrow vascular endothelial cells. This results in rolling on
endothelial (E) and platelet (P) selectins, which is followed by firm
shear resistant adhesion to the vessel wall.12-14 These
interactions are mediated through the coordinated action of adhesive
molecules and activation processes triggered specifically by chemokines
such as SDF-1 and vascular ligands, eg, intercellular adhesion
molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1).9-14 Following arrest on the bone marrow
microvasculature, stem cells extravasate through the endothelium and
into the hematopoietic compartment. The  2 integrin, lymphocyte
function associated antigen-1 (LFA-1), is involved in the spontaneous
transendothelial migration of immature human CD34+ cells in
vitro.15,16 Furthermore, SDF-1 activation of LFA-1 that is
present on human CXCR4+ T lymphocytes led to firm shear
resistant adhesion to endothelial ICAM-1.17 The major 1
integrins, very late activation antigen-4 (VLA-4), and VLA-5 have been
implicated in the adhesive interactions of human, primate, and mouse
stem cells with the bone marrow extracellular matrix (ECM) and stromal
cells.18-22
In the present study, we investigated both specific and overlapping
adhesive functions of LFA-1, VLA-4, and VLA-5 in interactions between
immature human CD34+/CXCR4+ cells and the
vascular endothelial, ECM, and stromal elements of the bone marrow. The
role of the major stem cell chemokine SDF-1 in either triggering
adhesiveness of these integrins or in directing human SRCs/stem cells
to migrate across the different bone marrow compartments, which express
ligands to these integrins, was investigated. We tested the ability of
CD34+/CXCR4+ cells, which migrate in vitro
across human endothelial and stromal cells toward SDF-1, to engraft and
repopulate NOD/SCID mice in vivo through the combined activities of
these integrins.
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Materials and methods |
Reagents
The following reagents were used in this study: human ICAM-1 (gift
of Dr L. Klickstein, Brigham and Women's Hospital, Boston, MA);
recombinant soluble human VCAM-123 and monoclonal
antibody (mAb) to VCAM-1 (gift of Dr R. Lobb, Biogen, Cambridge, MA);
human SDF-1 and macrophage inflammatory protein-1 (MIP-1) (R&D
Systems, Minneapolis, MN); bovine serum albumin (BSA,
fraction V), calcium- and magnesium-free Hank's balanced
salt solution (HBSS), ethylenediaminetetraacetic acid (EDTA), and
4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (Sigma, St
Louis, MO); human serum albumin (HSA) (Calbiochem, La Jolla, CA); human
fibronectin (FN) (Chemicon, Temecula, CA); and collagen type I
(laminin) (Cellagen; ICN Pharmaceuticals, CA).
Human and mouse cells
Human cord blood cells were obtained from full-term deliveries after
informed consent and were used in accordance with approved procedures
by the human experimentation and ethics committees of the Weizmann
Institute, Rehovot, Israel. Cord blood samples were diluted in
phosphate-buffered saline (PBS) and supplemented with 1% fetal calf
serum (FCS) (Bet Haemek, Israel). Low-density mononuclear cells (MNCs)
were collected after standard separation on Ficoll-Paque (Pharmacia
Biotech, Uppsala, Sweden) and washed with PBS. Human umbilical vascular
endothelial cells (HUVECs) were isolated from umbilical cord
veins according to the method of Jaffe et al.24 Human
adherent stromal cells were prepared and grown as previously
described25 from leftover bone marrow cells for allogeneic
transplantation. Mouse stromal cell lines were grown as previously
described.26
Enrichment of human CD34+ cells
Enrichment of human CD34+ cells was performed with a
magnetic bead separation kit (mini-MACS, Miltneyi Biotec, Bergisch
Gladbach, Germany) according to the manufacturer's instructions. The
purity of the enriched CD34+ cells was 60%-85% when cells
were passed over 1 column and more than 98% when the cells were passed
over 2 columns.
Flow cytometry analysis
Flow cytometry analysis was done as previously
described.8 Bone marrow cells from mice that received
transplantations were flushed and resuspended in staining buffer (PBS,
0.1% BSA, and 0.02% sodium azide) after red blood cells were lysed
with ammonium chloride, and 105 cells were incubated with
10 µ/mL purified antimouse CD16/CD32 Fc receptor (FcR)
(PharMingen, San Diego, CA) and 1% human plasma for 20 minutes at 4°C. Cells were stained with human-specific direct-labeled antibodies and incubated for 30 minutes on ice. Isotype
control antibodies (Becton Dickinson, San Jose, CA) were used to
exclude false-positive cells. Murine bone marrow cells from
nontransplanted mice were used a negative control, and human cells were
used as a positive control. Dead cells were gated out by staining with
propedium iodide (Sigma). Immature human cells from engrafted mice were
identified by double-staining with anti-CD34 fluorescein isothiocyanate
(FITC) (Becton Dickinson) and anti-CD38 phycoerythrin (PE) (Coulter
Electronics, Miami, FL) and the presence of pre-B-lymphoid cells by
anti-CD45 FITC (IQP, The Netherlands) and anti-CD19 PE (Coulter Electronics).
The levels of CXCR4 expression on human CD34+ cells were
detected with anti-CXCR4 PE (PharMingen) together with anti-CD34 FITC. The levels of immature cells in the transwell migration assay were
analyzed by staining with anti-CD34 FITC and anti-CD38 PE. After
staining, cells were washed twice in the same buffer and analyzed by
fluorescence-activated cell sorter (FACS) (FACSort and CellQuest
software, Becton Dickinson). When antibodies to VCAM-1 and ICAM-1
(Novocastra Laboratories, Newcastle, England) were used, they were
detected by using secondary FITC-conjugated F(ab')2 fragment goat
antimouse immunoglobulin G (IgG) (Jackson, West Grove, PA).
Hematopoietic colony assay
Semisolid progenitor cultures specific for human colonies were
performed as previously described.5 In brief,
200 × 103 bone marrow cells per mL from
transplanted mice were plated in 0.9% methylcellulose (Sigma), 15%
FCS, 15% human plasma, 50 ng/mL stem cell factor, 5 ng/mL
interleukin-3 (IL-3), 5 ng/mL granulocyte-macrophage-colony stimulating factor (GM-CSF) (R&D Systems), and 2 U/mL erythropoietin (EPO) (Ortho Biotech, Don Mills, Ontario, Canada). The cultures were
incubated at 37°C in a humidified atmosphere containing 5% carbon
dioxide (CO2) and were scored 14 days later.
Mice
NOD/SCID mice (NOD/LtSz
PrKdcscid/PrKdscid)
were bred and maintained under defined flora conditions in individually
ventilated (high-efficiency particle-arresting filtered air) sterile
microisolator cages (Techniplast, Italy) at the Weizmann Institute. All
the experiments were approved by the animal care committee of the
Weizmann Institute. The 8-week-old mice were irradiated with a
sublethal dose of 375 cGy (67 cG/min) from a cobalt source prior to
transplantation. Human CD34+ enriched cells
(2 × 105 cells per mouse; purity, 60%-98%), were
injected into the tail vain of irradiated mice in 0.5 mL Roswell Park
Memorial Institute medium (RPMI 1640) with 10% FCS. For in vivo
blocking experiments, the cells were first preincubated for 30 minutes
on ice with 5 µg/mL antihuman CD34 antibodies as a negative control
(Becton Dickenson) or the following mAbs (Serotec, Oxford,
England): anti-1 (MCA1188), VLA-4 (MCA697), VLA-5 (MCA1187), or
anti-LFA-1 (MCA1149). The cells were washed and injected into mice,
which were killed after 30-45 days. The cells from the femur, tibia,
and pelvis bones were flushed with a syringe.
Chemokine and chemotaxis assays
Chemotaxis experiments were assayed (Costar, Cambridge, MA) by using
transwells (diameter, 6.5 mm; pore, 5 µm) as previously described.8 We added 100 µL chemotaxis buffer (RPMI 1640 with 1% FCS) containing 2 × 105 CD34+
cells to the upper chamber, and 0.6 mL chemotaxis buffer with or
without 125 ng/mL SDF-1 or MIP-1 to the bottom chamber. After 4 hours, migrating (bottom chamber) and nonmigrating (upper chamber) cells were counted for 30 seconds using a FACSort. Endothelial or bone
marrow stromal cells (2 × 104 cells per well) were
seeded into the upper chamber, precoated with 25 µg/mL FN for 1 hour
at room temperature, and grown for 48 hours. In some experiments,
106 CD34+ cells per mL were preincubated (30 minutes at 4°C) in 100 µL migration buffer containing either 5 µg control isotype-matching mAb (Becton Dickinson) or a murine mAb
specific either to 4 or to LFA-1 (Serotec). The cells were washed
before transendothelial or transstromal migration. Endothelial and
stromal cells were activated by overnight incubation with 2 ng/mL
TNF- (R&D Systems), which was washed before the migration.
Cell adhesion assay
PBS (500 µL) containing 20 µg/mL human FN or 2.5% BSA as
control was placed in 24-well plates (Falcon, Becton Dickinson) and incubated overnight at 4°C. Wells were washed with PBS, blocked with 1000 µL 2.5% BSA in PBS, and incubated for 1 hour at room temperature. Plates were then washed 3 times with adhesion medium (RPMI
1640 supplemented with 0.2% BSA). CD34+ enriched
cells (6 × 104 cells) in 200 µL adhesion medium
were added to the precoated wells. The cells were allowed to adhere for
30 minutes at 37°C in a humidified atmosphere containing 5%
CO2 and then washed 4 times with prewarmed adhesion
medium to remove nonadherent cells. The adherent cells were collected
with medium containing 0.01% EDTA and by gentle shaking with vortex.
The cells were counted and assessed for colony forming cells (CFCs).
Controlled detachment adhesion assay
Laminar flow assays were performed as previously
described.27 ICAM-1 and soluble VCAM-1 were coated at 10 µg/mL in the presence of 2 µg/mL HSA carrier on polystyrene plates
(Becton Dickinson). The plates were washed 3 times with PBS and blocked
with 20 µg/mL HSA in PBS for 2 hours at room temperature.
Alternatively, washed plates were coated with 10 µg/mL SDF-1 in PBS
for 30 minutes at room temperature before being blocked with HSA. The
plates were assembled as the lower wall of a parallel wall flow chamber
and mounted on the stage of an inverted microscope. Cord blood
2 × 106 CD34+ cells per mL (purity, at
least 98%) were suspended in binding buffer, perfused into the
chamber, and allowed to settle on the substrate-coated chamber wall for
1 minute at 37°C. Flow was initiated and increased in 2-fold to
2.5-fold increments every 5 seconds, thereby generating controlled
shear stresses on the wall. Cells were visualized with an inverted
phase-contrast Diaphot Microscope (magnification objective × 20)
(Nikon, Tokyo, Japan) and photographed with a long
integration LIS-700 CCD video camera (Applitech, Holon, Israel)
connected to an AG-6730 S-VHS video recorder (Panasonic, Osaka, Japan).
The number of adherent cells resisting detachment by the elevated shear
forces was determined after each interval by analysis of videotaped
cell images and was expressed as the percent of originally settled
cells. To test the effects of phorbol 12-myristate 13-acetate
(PMA), cells were suspended in binding medium containing 100 ng/mL PMA (Sigma) seconds before being perfused into the chamber.
All adhesion experiments were performed at least 3 times on multiple
test fields.
Real-time tracking of CD34+ cell migration in 3-D
extracellular matrix-like gels
Migration assays in 3-D ECM-like gels were performed as previously
described.28 Purified (at least 98%) cord blood
CD34+ cells were suspended in a 10-µL drop consisting of
1.8 µg/mL collagen type I (6 µg/mL laminin) and 2.5 µg/mL FN in
RPMI 1640. A second drop without cells was placed 1.5 mm
from the first drop. An SDF-1 depot was created in a third drop, which
was supplemented with 500 ng/mL SDF-1 and placed 1.5 mm downstream from
the second drop and 3-5 mm from the first drop. Once the drops began to
polymerize, they were gently connected with a fine needle to form a
continuous 3-D gel, and cell migration within this gel was tracked by
time-lapse video microscopy. Cell images were visualized and videotaped
on an AG-6730 S-VHS time-lapse video recorder at 25 frames per minute. The proportions of polarized, nonmotile, randomly migrating, and directionally migrating cells within the entire population of cells in
the field were determined within 60-90 minutes of tracking. The role of
1 integrins was examined by preincubating 106
CD34+ cells per mL for 20 minutes at 4°C in a 200 µL
RPMI 1640 mixture containing 1% BSA and either 5 µg control
isotype-matching mAbs or specific murine mAbs to either the 4, 5,
or 1 integrins. Subsequently, the cells were washed and added to the
3-D gels.
| |
Results |
SDF-1 activates the integrins LFA-1 and VLA-4 on
CD34+/CXCR4+ cells to bind their
respective endothelial ligands ICAM-1 and VCAM-1
Immature human cord blood CD34+/CXCR4+ cells
express the major integrins LFA-1, VLA-4, and VLA-5 on their surface
(Figure 1A and 1B). The adhesiveness of
integrins to endothelial ligands was measured in integrin-dependent
adhesion assays using a parallel-plate flow chamber, which simulates
blood flow. Purified cord blood CD34+ cells treated briefly
with PMA or left untreated were allowed to bind for 1 minute to
immobilized ICAM-1 and VCAM-1 in stasis. Alternatively, the cells were
briefly allowed to interact with ICAM-1 and VCAM-1 coimmobilized with
SDF-1. The cells were then subjected to incremented shear flow that
generated increasingly detached forces on the adherent cells. SDF-1
rapidly activated the firm shear-resistant adhesion of human
CD34+/CXCR4+ cells to immobilized ICAM-1 and
VCAM-1 (Figure 1C and 1D). Chemokine-mediated activation was almost as
powerful as activation with the nonphysiological agonist PMA, and the
activation was specific because it was totally inhibited in the
presence of the integrin inhibitor EDTA (Figure 1C and 1D).
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| Fig 1.
Results of staining, double-staining, or
untreated enriched CD34+ cells.
(A) CXCR4 expression on enriched CD34+ cells stained with
antibodies to CD34 FITC and CXCR4 PE. (B) Double-staining
of enriched CD34+ cells with PE-labeled antibodies to CXCR4
and FITC-labeled antibodies to each of the major integrins: LFA-1,
VLA-4, and VLA-5. CXCR4+ cells within the CD34+
population were gated, and the levels of staining for LFA-1, VLA-4, and
VLA-5 are shown. The solid histogram indicates negative control
staining (CTRL) with isotype control antibody. (C, D) Untreated (CTRL),
100 ng/mL PMA, or EDTA pretreated with cord blood CD34+
cells were perfused into a parallel plate flow chamber and allowed to
settle for 1 minute at 37°C on substrates coated with (C) VCAM-1 or
(D) ICAM-1. SDF-1: Plates were coated with (C) VCAM-1 or (D) ICAM-1 in
combination with SDF-1. CTRL: Plates were coated with HSA. The data in
(A) and (B) are from a representative experiment. The data in (C) and
(D) are the average of 3 experiments plus or minus SE. (*Indicates
P < .05).
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SDF-1-induced transmigration of
CD34+/CXCR4+ cells through vascular
endothelial cells is dependent on LFA-1 and VLA-4
Following their firm adhesion to the vessel wall, stem cells
extravasate through the endothelial lining of the vasculature. We
further studied the role that SDF-1 plays in regulating the extravasation of immature human CD34+/CXCR4+
cells through endothelial cells. This was accomplished through transendothelial migration assays using 2 types of TNF--activated endothelial cells: HUVECs or the murine bone marrow-derived
endothelial cell line, MBA-2.1.24,26 Upon activation with
TNF- in vivo, both cell types significantly up-regulated ICAM-1 and
VCAM-1 surface expression, mimicking the constitutive expression of
these ligands by bone marrow endothelium (Figure
2A). CXCR4-dependent migration of cord
blood CD34+ cells occurred across activated HUVECs toward a
chemotactic gradient of SDF-1 in a transwell assay. This migration was
partially blocked by antibodies to LFA-1, but it was not inhibited by
antibodies to VLA-4 or VLA-5, and no additive effect was observed when
all the antibodies were used together (Figure 2B). Surprisingly,
antibodies to VLA-4 partially inhibited transendothelial migration by
CD34+/CXCR4+ cells only when bone
marrow-derived MBA-2.1 endothelial cells were used. We found no effect
when antibodies to VLA-5 were used; however, an additive effect was
observed when antibodies to LFA-1, VLA-4, and VLA-5 were mixed together
(Figure 2B). These results may suggest that stem cell migration through
endothelium depends on the origin of the endothelial cells and the
levels of VCAM-1 expression (Figure 2B).
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| Fig 2.
SDF-1-induced transendothelial migration of human
CD34+ cells.
(A) Up-regulation of VCAM-1 (upper panels) and ICAM-1 (lower panels) by
TNF- on HUVECs or MBA-2.1 cells. Isotype control (IC);
untreated cells (U); and TNF--treated cells (TNF-) were stained
with antibodies to VCAM-1 or ICAM-1. (B) CD34+ cells were
incubated with neutralizing antibodies to LFA-1, VLA-4, VLA-5, or all
together prior to migration through TNF- preactivated endothelial
cells toward SDF-1. (C) Migrating (M) and nonmigrating (NM) cells
through MBA-2.1 toward SDF-1 were stained with antibodies to CD34 and
CD38. (D) Percent engraftment by migrating (M) and nonmigrating (NM)
cells in the murine bone marrow 1 month following transplantation,
quantified by FACS analysis using antibodies to human CD45. Each dot
represents 1 mouse. Numbers and bars indicate the engraftment averages
plus or minus SE. (*Indicates P < .05.) (Experiment I [E
I]) The presence of human progenitors in the bone marrow of mice
transplanted with migrating (M) or nonmigrating (NM) cells. The shaded
square indicates colony forming unit-granulocyte/macrophage (CFU-GM)
cells; the open square indicates burst forming unit-erythroid (BFU-E),
and the solid square indicates multilineage colony
(CFU-GEMM). (E II) The levels of human lymphoid
CD45+/CD19+ pre-B cells in the bone marrow of
mice transplanted with migrating (M) cells.
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Next, the cell surface phenotype of migrating and nonmigrating
CD34+ cells (designated M and NM, respectively, in Figure
2) was characterized. SDF-1 preferentially induced transmigration of
primitive
CD34+/CD38 /low/CXCR4+
cells across the endothelium (Figure 2C). Notably, cells migrating through the endothelial cells gave significantly higher levels of
engraftment compared with nonmigrating cells collected from the upper
chamber (Figure 2D). Bone marrow cells from mice engrafted with
migrating cells gave rise to high levels of both myeloid CFCs (Figure
2E I) as well as lymphoid CD19+ pre-B cells (Figure 2E
II). Mice transplanted with nonmigrating cells did not contain human
progenitor CFCs (Figure 2E I). We therefore conclude that SDF-1 can
selectively induce the transendothelial migration of the human SRC/stem
cell subset within the CD34+ progenitor cell population.
The extravasation of CD34+ cells through the ECM
is dependent on VLA-4 and VLA-5
Following extravasation through the vascular endothelium, stem cells
encounter the bone marrow ECM barriers. In contrast to SDF-1, other
chemokines, such as MIP-1,29-31 are poor
chemoattractants of human CD34+ progenitor cells (Figure
3A). However, both SDF-1 and MIP-1 can
activate the binding of CD34+ cells to the ECM protein FN
(Figure 3B). Furthermore, both chemokines preferentially induce the
binding of immature multilineage CFCs to FN (Figure 3C).
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| Fig 3.
SDF-1 is a more potent chemoattractant for immature CFCs
than MIP-1 .
(A) Spontaneous migration of CFCs (CTRL) and migration toward SDF-1 or
MIP-1 in a transwell assay. (B) Adhesion of
CD34+ cells to BSA (CTRL) or FN- coated wells and FN with
SDF-1 or MIP-1. (C) Quantification of CFC levels in the adherent
CD34+ cell populations. (D) Percent inhibition of
CD34+ cell adhesion to FN, by antibodies to VLA-4 or VLA-5,
in the presence or absence of SDF-1 and MIP-1. The results shown
represent the average of 3 different experiments plus or minus SE.
(*Indicates P < .05).
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FN is part of the basal lamina underlining the endothelial cells and is
also present in the bone marrow extravascular space. To unravel the
mechanism by which SDF-1 regulates the interactions between cord blood
CD34+/CXCR4+ cells and FN, we studied the
contribution of the major integrins VLA-4 and VLA-5 to binding of these
cells to FN. Adhesion of CD34+ cells to FN was mainly
dependent on VLA-5. Activation of the cells with SDF-1 or
MIP-1 caused enhanced dependency on VLA-5, which suggests that in
this case, VLA-5 but not VLA-4 is the major FN receptor (Figure 3D).
During bone marrow transplantation, stem cells need to pass through the
basal lamina, which is composed of the ECM proteins laminin, collagen,
and FN. SDF-1-mediated interactions between migrating human cord blood
CD34+/CXCR4+ cells and the ECM were studied in
vitro by monitoring the migratory properties of these cells through a
3-D ECM-like gel that was reconstituted with a meshwork of laminin,
collagen, and FN. This novel system allows for close examination of the
random and directional migration of cells toward a newly generated
chemoattractant source in real time.28 Most
CD34+ cells embedded in this gel remained spherical and
failed to polarize or migrate in the absence of SDF-1 (Figure
4A). However, upon introduction of an SDF-1
gradient, 40% of the cells polarized in a time-dependent manner
(Figure 4A). As many as 30% of the cells migrated toward a gradient of
SDF-1 (Figure 4B). The percentage of polarized and migrating
CD34+ cells in a 3-D ECM-like gel correlated with the
levels of CXCR4 expression on cord blood CD34+ cells (48%
positive cells) (Figure 1A) and with the frequency of 20%-30% of
cells migrating toward a gradient of SDF-1 (Figure 2B). In contrast to
the dominant role of VLA-5 in facilitating the static adhesion to FN,
SDF-1-induced polarization and directional migration of
CD34+/CXCR4+ cells in 3-D ECM-like gels was
dependent on both VLA-4 and VLA-5 integrins (Figure 4A and 4B). Thus,
weak VLA-4 adhesion/deadhesion interactions with FN
during migration across 3-D ECM-like gels are as important as
interactions between VLA-5 and FN. Antibodies to LFA-1 had no
effect on SDF-1- induced polarization and migration of the
cells (Figure 4 A and 4B).
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| Fig 4.
Dependence of SDF-1-induced polarization and directional
migration of CD34+ cells through ECM on VLA-4 and VLA-5.
(A) Polarization and (B) migration of CD34+ cells.
The control ( ) was done without a gradient of SDF-1;
 indicates a gradient of SDF-1. The cells were quantified in 3-D
ECM-like gels without or with the following: anti-VLA-4 mAb ( ),
anti-LFA-1 mAb ( ), or anti-VLA-5 mAb ( ). The average of 3 different experiments plus or minus SD are shown. (C, D) Contribution
of 1 and 2 integrins to the engraftment of CD34+
cells in NOD/SCID mice. Percent engraftment in the murine bone marrow
by cord blood CD34+ cells pretreated with antibodies to
either LFA-1, VLA-4, VLA-5, 1, VLA-6, or CD34, quantified after (C)
6 weeks or (D) 4 weeks by immunostaining with antihuman CD45 mAb. (C)
Each point represents 1 mouse. (D) Results were pooled from 3 different
experiments.
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We demonstrated above that SDF-1 activates the major integrins LFA-1,
VLA-4, and VLA-5 in a specific manner during SRC/stem cell migration
across endothelial cells and ECM. To determine the in vivo role of the
major integrins LFA-1, VLA-4, and VLA-5 during the engraftment process
of human SRCs/stem cells, enriched CD34+ cord blood cells
were pretreated with antibodies against each of the above integrins
separately or as a control with anti-CD34 and anti-VLA-6 antibodies
before transplantation. Neutralizing antibodies to 1, VLA-4, or
VLA-5 blocked murine bone marrow engraftment by human CD34+
cells, whereas control anti-CD34 or anti-VLA-6 antibodies did not.
This demonstrated a major role for these integrins in the engraftment
process (Figure 4C and 4D). Neutralizing antibodies to LFA-1
significantly decreased the levels of engraftment (Figure 4C). Thus
anti-LFA-1 antibodies caused partial inhibition of engraftment, and
anti-VLA-4 or anti-VLA-5 antibodies mediated near-complete inhibition
of human SRC/stem cell engraftment. Taken together, this data strongly
suggest that LFA-1, VLA-4, and VLA-5 function in a sequential or
consecutive manner, which is mediated by SDF-1, to support the
recruitment of stem cells into the bone marrow.
Selective migration of human SRCs/stem cells induced by SDF-1
across mesenchymal stromal cells
Once stem cells have crossed the ECM barrier, they then interact
with the bone marrow mesenchymal microenvironment. The ability of SDF-1
to induce this crucial step in stem cell trafficking within the bone
marrow stromal microenvironment was tested by examining the migration
of immature CB CD34+/CXCR4+ cells through bone
marrow-derived murine stromal cells (adipocyte 14F1.1 and osteoblast
MBA-15.1 cell lines) or primary human stromal cells.25,26
In contrast to endothelial cells, stromal cells express only low levels
of ICAM-1 or VCAM-1, and the expression of these adhesion molecules was
not affected by TNF- (data not shown). Similar levels of
CD34+/CXCR4+ cells migrated through endothelial
and stromal cells in response to SDF-1 (Figure 2B and Figure
5A). However, the migration of CD34+ cells through the stromal layer is dependent on both
integrins VLA-4 and VLA-5 but not on LFA-1 (Figure 5A). As observed in
transendothelial migration induced by SDF-1, this chemokine
preferentially induces transmigration across stromal cells of primitive
CD34+/CD38/low/CXCR4+ cells
(Figure 2B and data not shown). We further tested the ability of
CD34+/CXCR4+ cells that migrated through the
different stromal cells to engraft irradiated NOD/SCID mice. Cells
migrating through the stroma layers gave significantly higher levels of
engraftment compared with nonmigrating cells collected from the upper
chamber (Figure 5B). Moreover, multilineage differentiation of
engrafted SRCs/stem cells, which included lymphoid CD19+
pre-B cells (Figure 5C I), primitive
CD34+/CD38/low cells (Figure 5C II), and
myeloid CFCs (data not shown), was achieved only by migrating cells. We
therefore conclude that SDF-1 preferentially induces the transstromal
migration of human SRCs/stem cells.
View larger version (34K):
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[in a new window]
| Fig 5.
SDF-1-induced transstromal migration of human SRCs.
(A) Migration of CD34+ cells across murine bone
marrow-derived adipocyte 14F1.1 and MBA-15 stromal cells and primary
human stroma (HS) cells toward SDF-1 is dependent on VLA-4 and VLA-5
but not on LFA-1. (B) Percent engraftment in the murine bone marrow by
nonmigrating (NM) and migrating (M) cells, quantified 1 month after
transplantation by FACS analysis using antibodies to human CD45. Each
dot represents 1 mouse, and bars and numbers indicate the average time
of engraftment. (*Indicates P < .05.) (C) Phenotype
analysis of engrafted human cells in mice transplanted with
transstromal migrating (M) cells. Lymphoid
CD45+/CD19+ pre-B cells (EI, R1), as well as
primitive CD34+/CD38/low cells (EII,
R2), are shown.
|
|
| |
Discussion |
In the present study we demonstrate that the major integrins VLA-4,
VLA-5, and LFA-1 are present in immature human CD34+ cells
and that they are functionally activated by SDF-1. In addition, neutralizing antibodies to LFA-1 significantly reduced the levels of
engraftment, and neutralizing antibodies to either VLA-4 or VLA-5 fully
blocked the engraftment of the murine bone marrow by human SRCs/stem
cells. These results, together with previous results which demonstrated
that engraftment of human SRCs/stem cells is dependent on SDF-1/CXCR4,
suggest that activation of the major integrins VLA-4, VLA-5, and LFA-1
on SRCs/stem cells by SDF-1 is essential for the multistep process of
migration and engraftment.
In vitro studies have shown that spontaneous transendothelial migration
of human CD34+ cells through HUVECs is dependent on
LFA-1.15,16 Furthermore, anti-LFA-1 blocking antibodies
completely prevented the IL-8-induced mobilization of murine
hematopoietic stem cells.32 We demonstrate here that
SDF-1-dependent transendothelial migration is partially dependent on
LFA-1 (Figure 2B). These results suggest a role for LFA-1 in the
process of homing and engraftment of hematopoietic stem cells. However,
murine hematopoietic stem cells with radioprotective capacity can be
both positively or negatively stained for LFA-1.33 Moreover, it has been reported that CD34+ LFA-1 cells
express LFA-1 within 24 hours in culture or during treatment with
various cytokines.34 We have shown that the levels of
ICAM-1 and VCAM-1 on endothelial cells differ between bone marrow and
HUVECs (Figure 2A). In another study we found that SDF-1 is expressed
by human bone marrow endothelial cells.35 This result was
confirmed by others who also demonstrated that murine lung endothelial
cells do not express SDF-1, which suggests that homing to the bone
marrow is initiated by endothelial-bound SDF-1.36
In the present study we discovered that LFA-1 is involved in the
SDF-1-dependent transendothelial migration of
CD34+/CXCR+ cells and in the engraftment of
human SRCs/stem cells. Concomitantly, SDF-1 is capable of activating
shear-resistant adhesion of CD34+/CXCR+ cells
to ICAM-1. These results suggest that during the process of
engraftment, LFA-1/ICAM-1 interactions are needed. The type of
interactions between repopulating SRCs/stem cells and the recipient adherent cells appears to be determined by the repertoire of adhesion molecules expressed by the given endothelial or stromal cell. We found
that antibodies to VLA-4 can partially block SDF-1-induced migration
of CD34+/CXCR4+ cells through an endothelial
cell layer formed by bone marrow-derived cell line MBA-2.1 but not
through HUVECs. This fact and recently published results suggest a role
for VLA-4/VCAM-1 in the extravasation process.37 Moreover,
there is the possibility that the levels of VCAM-1 expressed by
endothelial cells determine its usage by repopulating
CD34+/CXCR4+ cells.
The involvement of SDF-1 in the rapid physiological shift from rolling
behavior on endothelial cells to firm ICAM-1/LFA-1-dependent arrest of
human CD4+ T lymphocytes suggests a similar mechanism of
action for SDF-1 in the control of migrating
CD34+/CXCR+ cells.38,39 Indeed, in
this study, SDF-1 stimulated an integrin-mediated arrest of immature
human CD34+ cells on vascular endothelium under shear
flow.35 Interestingly, transendothelial migration of human
CD34+ cells to a gradient of SDF-1 was also demonstrated to
be dependent on E selectin.40 In contrast to
transendothelial migration, transstromal migration of CD34+
cells in response to SDF-1 is dependent on VLA-4 and VLA-5 but not
LFA-1 (Figure 5). However, the role of SDF-1 and integrins in the
extravasation process under shear flow and in the microenviromental localization of stem cells is still obscure.
Migration of CD34+/CXCR4+ cells through the ECM
is dependent on both VLA-4 and VLA-5 (Figure 4). VLA-4, which binds to
FN and VCAM-1, as well as VLA-5, which binds to the
arginine-glycine-aspartic acid amino acid sequence (RGD) of
FN, are believed to be important mediators of direct interactions
between stem cells and the bone marrow
microenvironment.18-20 Blocking antibodies against VLA-4 and VLA-5 inhibit the formation of day 12 spleen colonies by murine stem cells.41 Moreover, blocking antibodies to VLA-4 were
recently shown to inhibit the homing of human CD34+ cells
into the bone marrow of fetal sheep.42 VLA-5 is expressed by mouse stem cells and human long-term SCID repopulating cells and
can also mediate their adhesion to FN.22 The role that such interactions play in the process of human stem cell repopulation, as
well as the exact site at which such interactions occur, is unknown. In
our studies, static adhesion of CB CD34+ cells and CFCs to
FN is mainly mediated by VLA-5 but not VLA-4 (Figure 4). However, when
fetal liver or bone marrow CD34+ cells were used, both
integrins were equally important for the adhesion to FN.43
In contrast to static adhesion of cord blood CD34+ cells,
SDF-1-induced polarization and directional migration of CD34+/CXCR4+ cells in 3-D ECM-like gels is
dependent on both VLA-4 and VLA-5. Thus, the process of migration is
different from adhesion, and weak adhesion-deadhesion interactions
between VLA-4 and its FN ligands are essential for the migration
processes but not for firm adhesion interactions. It is therefore
possible that VLA-5 is activated more in the initial stages of
adhesion to the ECM, whereas both integrins are needed for the movement
of cells through the ECM.
Our data suggest that during development and in clinical bone marrow
transplantation, migration of human stem cells to and within the bone
marrow microenvironment is mediated by SDF-1. Interestingly, the bone
marrow of mice transplanted with fetal liver cells from CXCR4-deficient
murine fetuses was engrafted. However, the levels of donor-derived
multilineage hematopoiesis in the bone marrow of these mice was
significantly reduced.44,45 Furthermore, CXCR4-null fetal
liver cells recovered from the bone marrow of primary transplanted mice
failed to repopulate secondary recipients.45 These results
demonstrate that long-term repopulation by pluripotent stem cells
capable of homing to the bone marrow and high levels of multilineage
engraftment of primary and secondary transplanted recipients are absent
in CXCR4-null fetal liver cells. CXCR4-null fetal liver cells can home
to the bone marrow independently of CXCR4, but fail to proliferate and
differentiate in the absence of CXCR4.
Broxmeyer et al46 have created a transgenic SDF-1 mouse and
have found that SDF-1 is a survival factor for murine stem cells. In
another study SDF-1 was also found to be a survival factor for human
CD34+ cells.47 The small population of human
SCID repopulating stem cells and primitive human stem cells capable of
repopulating preimmune sheep were lately shown to be vascular
endothelial growth factor receptor 2 (VEGFR2/KDR).48
Studies done by Peichev et al49 and confirmed by us (data
not shown) have shown that all the human hematopoietic
CD34+ KDR+ cells are also
CXCR4+. Furthermore, CXCR4 was also shown to be
essential for the homing and engraftment of NOD/SCID mice by malignant
human pre-B-acute lymphoblastic leukemia (ALL) cells, and its
expression levels correlated with the NOD/SCID mice repopulating
potential of human acute myeloid leukemia (AML) cells.50,51
We and others have found that SDF-1, like ICAM-1 and VCAM-1, is
specifically expressed on human bone marrow endothelial
cells.35,36 We have also shown that SDF-1 can convert the
rolling of CD34+ cells on endothelial cells into
arrest.35 In addition, total body irradiation or
conditioning with cytotoxic drugs, which are needed for stem cell
transplantation, also significantly increases the levels of SDF-1
produced by bone marrow stromal cells.52 Lastly, homing of
human CD34+ SRCs/stem and progenitor cells to the murine
bone marrow or spleen is dependent on SDF-1 and CXCR4.53 It
is evident, therefore, that CXCR4/SDF-1 interactions promote the homing
and engraftment of human stem and progenitor cells. Alternative
mechanisms of homing and engraftment by pluripotent stem cells may also
exist. However, they are secondary to the SDF-1/CXCR4 pathway because CXCR4-null fetal liver cells lack true stem cell properties, and both
SDF-1-null and CXCR4-null embryos have impaired bone marrow hematopoieis.
Based on our studies, we suggest the following scenario for the homing
of human SRCs/stem cells to the bone marrow. Transplanted human
CD34+/CD38/low/CXCR4+
SRCs/stem cells that express LFA-1, VLA-4, VLA-5, and E and P selectin
ligands54 reach the bone marrow and are recruited to specific vascular sites that constitutively express E/P selectin, ICAM-1, and VCAM-1. Upon activation with endothelium expressing or
presenting SDF-1, LFA-1 and VLA-4 are activated on rolling stem cells
to support their firm adhesion to the vessel wall. In response to
SDF-1, the arrested human stem cells extravasate into the bone marrow
ECM compartment (diapedesis) using LFA-1 and VLA-4. In the
extravascular space, by using VLA-4 and VLA-5 for movement across FN,
the stem cells polarize and migrate through the basal lamina toward
local gradients of SDF-1, which are produced by specialized stromal
cells, and orient themselves through the different elements of the bone
marrow microenvironment and into the "stem cell niches" (Figure
6).
View larger version (139K):
[in this window]
[in a new window]
| Fig 6.
Stem cell rolling interactions, SDF-1 interactions, and
migrating stem cells.
(A) Stem cell rolling interactions on constitutively expressed
endothelial E and P selectins. Following rolling, CXCR4+
stem cells (blue cells) are activated by SDF-1, which is secreted from
bone marrow endothelial cells and triggers LFA-1/ICAM-1 and
VLA-4/VCAM-1 interactions to support firm adhesion to endothelial
cells. (B) Cells that do not express sufficient levels of CXCR4
(purple) will detach from the endothelial layer and return to the blood
stream. (C) The arrested human CXCR4+ stem cells, in
response to SDF-1, will extravasate and migrate through the underlying
basal lamina ECM using VLA-4 and VLA-5 integrin receptors to FN. (D)
Migrating stem cells will eventually reach the "stem cell
niches," which consist of stromal cells that present the proper set
of adhesion molecules (eg, VCAM-1 and FN), SDF-1, and growth
stimulatory factors.
|
|
In summary, we further identify repopulating human SRCs/stem cells as
functionally expressing the integrins LFA-1, VLA-4, and VLA-5 both for
migratory and adhesion processes triggered by endothelial- or
stromal-associated SDF-1. Furthermore, our in vitro and in vivo data
suggest a chemokine-dependent differential role for these major
integrins in the multi-step process of migration, engraftment, and
retention of human SRCs/stem cells in the murine bone marrow microenvironment.
| |
Footnotes |
Supported in part by grants from the Israel Academy of
Science and the Israel Cancer Research Fund (T.L.), Israel; a grant from The Germany MINERVA (A.P.), Germany; and a grant from the Balfour
Peisner Bone Marrow Cancer Research Fund (I.P. and D.Z).
Submitted August 12, 1999; accepted January 19, 1999.
Reprints: Tsvee Lapidot, The Weizmann Institute of Science,
Department of Immunology, PO Box 26, Rehovot 76100, Israel; e-mail:
litsvee{at}weizmann.weizmann.ac.il.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction