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Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1196-1205
By
From the Department of Haematology, Royal Free Hospital School of
Medicine, London, UK and the Department of Haematology, University
College Medical School, London, UK.
The transmigration of hematopoietic progenitor cells (HPCs) across
vascular endothelium is a critical step in the homing of transplanted
stem cells, but the molecular basis for this is unknown. We used
mobilized peripheral blood CD34+ selected cells and
cultured bone marrow microvascular (BMECs) and human umbilical vein
endothelial cells (HUVECs) to investigate the adhesion and
transendothelial migration of HPCs. Colony-forming cells (CFCs) in
freshly isolated CD34+ cells showed high levels of
adhesion to both forms of endothelium (28% ± 4% and 38% ± 6% of
granulocyte-macrophage colony-forming cells [GM-CFCs] adhering to
HUVECs and BMECs, respectively), but were unable to migrate to any
significant extent across either (1.0% ± 0.3% and 1.1% ± 0.6%
of GM-CFCs migrating across HUVECs and BMECs, respectively). Greater
than 95% of peripheral blood CD34+ cells are in
G0/G1 of the cell cycle, but after 48 to 72 hours of stimulation with growth factors (interleukin-3 [IL-3] 12 ng/mL, stem cell factor 10 ng/mL, and IL-6 10 ng/mL), 28% ± 5% of
cells were in S+G2/M. Growth factor stimulation had no
effect on the adhesion of mobilized CFCs but resulted in enhanced
migration of these cells (9.8% ± 1.6% and 12.6% ± 3.1% of
GM-CFCs migrating across HUVECs and BMECs, respectively; P < .01, n = 6). Assessment of cell proliferation by the
3H-thymidine suicide method showed that, whereas 11.7% ± 3.3% of proliferating CFCs transmigrated across endothelium, only
1.3% ± 0.3% of nonproliferating CFCs did so (P < .05, n
= 5). Transmigration of growth factor-activated CFCs was inhibited by
anti-CD18 monoclonal antibody (MoAb; 50% ± 18% inhibition) and by
anti-platelet endothelial cell adhesion molecule-1 (PECAM-1) MoAb
(70.8% ± 7.1% inhibition; P < .05, n = 3). IL-1
stimulation of HUVECs had no significant effect on CD34+
cell transmigration, but caused marked enhancement of neutrophil migration. Stem cell homing may depend, in part, on the ability of
local cytokines to upregulate the transmigratory ability of these
cells. The transmigration of HPCs shares at least some molecular pathways with that of mature cells (CD18 and PECAM-1), but
is differently affected by endothelial activation.
THE ABILITY OF hematopoietic progenitor
cells (HPCs) and stem cells to selectively localize to the bone marrow,
the specialized microenvironment in which such cells are able to
reconstitute hematopoiesis in the host, provides the biological basis
for hematopoietic stem cell transplantation. Despite much advance in
our understanding of the inflammatory signals that regulate leukocyte
recruitment, the molecular mechanisms responsible for the selective
homing of HPCs to the bone marrow remain poorly understood. The
diapedesis of circulating HPCs from the bone marrow sinuses into the
marrow compartment itself is likely to occur as a multistep process, as
has been proposed for leukocyte homing to high endothelial venules or
to inflammatory sites.1,2 In this model, cells initially
roll on vascular endothelium tethered by selectins and their respective
ligands. Cell activation by signaling molecules, such as chemokines,
which are released by vascular and nonvascular cells, leads to
upregulation of integrin function, and the high affinity binding of
activated integrins to endothelial ligands produces tight adhesion,
shape change, and diapedesis to localize in extravascular
foci.2 The specificity of leukocyte extravasation in
inflammation, and of lymphocyte homing to peripheral tissues, is
considered to lie in recognition events involving cell surface receptors, primarily the selectins, and also
Diapedesed cells subsequently migrate within the bone marrow
compartment to localize in particular microenvironmental niches in
which the molecular mechanisms mediating anchorage also impart proliferative and differentiating signals. The adhesive components in
this last step have been the most studied, and various adhesion pathways, including VLA-4 binding to VCAM-1 and
fibronectin,11,12 CD44 binding to hyaluronic
acid,13 and Transendothelial migration of HPCs is a prerequisite for the
establishment and maintenance of hematopoietic tissue at anatomically distinct sites in the body and for the successful reconstitution of
hematopoiesis by infused stem cells. Although the extravasation of
mature cells, in particular phagocytic cells, is critically dependent
on the integrin family, CD11/CD18, patients suffering from the rare
leukocyte adhesion deficiency (LAD) do not have major problems with
hematopoiesis in contrast to the greatly impaired migration of
inflammatory cells.18 This raises the possibility that the
molecular basis for, as well as the regulation of, HPC transmigration
is distinct from that of mature cells. Such differences might lie in
the nature and function of bone marrow sinusoidal endothelium, but it
is not known if and how BMECs are specialized to support the
transmigration of primitive cells. Finally, cell migration involves
more than the engagement of cell surface receptors, for example,
control of actin assembly and disassembly is important,19 as is the redistribution and polarization of membrane structures. Cell
migration on vitronectin, for instance, has been shown to be critically
dependent on the ability of the cell to recycle specific membrane
receptors toward the moving edge of the cell in a highly regulated
endocytotic cycle, thus releasing adhesions at the rear of the cell and
providing a fresh source of membrane molecules for attachment at the
leading edge.20 The control of cell migration, a process
critical to the homing as well as the mobilization of HPCs, and the
egress of maturing cells may involve molecular pathways other than the
modulation of surface adhesion receptors.
In this study, we examined the ability of mobilized HPCs to migrate
across both specialized BMECs and the more undifferentiated human
umbilical vein endothelial cells (HUVECs) and the way in which this
migratory ability is regulated.
Materials
Cytokines.
Interleukin-1 Monoclonal antibodies (MoAbs).
Purified 60.3 (anti-CD18) was a gift from Dr John Harlan (University of
Washington, Seattle, WA), and 1.3 (anti-PECAM-1) was a gift from Dr P. Newman (Blood Research Institute, Milwaukee, WI). Fluorescein
isothiocyanate (FITC)- or phycoerythrin (PE)-conjugated MoAbs
(anti-CD54, anti-CD31, anti-VLA-4, anti-L-selectin, anti-CD45, and
anti-CD34) used for phenotyping were obtained from Becton Dickinson
(Oxford, UK).
Reagents.
RPMI 1640, Iscove's Modified Dulbecco's Medium (IMDM), fetal calf
serum (FCS), Penicillin/Streptomycin, and phosphate-buffered saline
(PBS) were obtained from Life Technologies (Paisley,
Scotland, UK). Trypsin/EDTA, fibronectin, and collagenase
(Clostridium histolyticum, type A) were obtained from
Boehringer Mannheim. 3H-thymidine (80 mCi/mL) was obtained
from Amersham (Little Chalfont, UK).
Endothelial Cells
Leukocytes
CD34+ Cell Purification CD34+-selected cells were obtained from patients with relapsed or resistant lymphoma undergoing peripheral blood stem cell transplantation or from normal donors. Local ethical committee approval for the study was in place, and informed consent was obtained from all patients. All subjects were mobilized with a protocol described previously.23 Low-dose cyclophosphamide (1.5 g/m2) was given on day 1 followed by G-CSF given subcutaneously at 10 µg/kg (filgrastim) or a single vial of lenograstim (263 µg/vial) 24 hours afterwards and daily thereafter until harvesting was complete. One to three apheresis collections were performed on days 8 to 12, on a Cobe Spectra (Cobe Laboratories, Gloucester, UK) commencing when the recovery white blood cell count was around 5.0 × 109/L. Single apheresis collections were processed for clinical scale CD34+ cell purification using a Ceprate SC immunoaffinity column (Cellpro Inc, Bothell, WA) and associated microprocessor device as previously described.24 Cytocentrifuge preparations of the final product were made for blast cell morphology, and the percentage of CD34+ cells was evaluated by alkaline phosphatase-antialkaline phosphatase immunoenzymatic staining as well as by dual immunofluorescence staining with anti-CD45-FITC and anti-CD34-PE and flow cytometry. The cell preparations had a median purity of 80% (range 52% to 95%).Immunofluorescent Flow Cytometry Immunofluorescence using flow cytometry and specific MoAbs was used to determine the expression of various surface markers, including adhesion molecules, on CD34+ cells. Aliquots (2 to 5 × 104 cells) were incubated with saturating concentrations of directly conjugated specific MoAbs for 45 minutes at 4°C, washed with cold PBS, and analyzed on a FACScan flow cytometer (Becton Dickinson). Negative controls were stained with isotype-matched IgG, and all samples were double stained with anti-CD34 MoAb.Clonogenic Assays in Methylcellulose Granulocyte/monocyte colony-forming cells (GM-CFCs) and burst-forming units-erythroid (BFU-E) were simultaneously evaluated in a methylcellulose-based clonogenic assay medium that consisted of Methocult (Stem Cell Technologies, Vancouver, Canada), with 20% IMDM and supplemented with IL-3 30 ng/mL, GM-CSF 25 ng/mL, G-CSF 25 ng/mL, SCF 10 ng/mL, and erythropoietin 2 U/mL. Purified CD34+ cells were set up in quadruplicate at 5.0 × 102/mL. Colonies were counted after 14 days incubation at 37°C in a humidified CO2 atmosphere.Adhesion and Transmigration of Leukocytes and Progenitor Cells In adhesion assays, confluent endothelial monolayers in 48-well plates were washed three times with warm medium before the addition of 51Cr-labeled neutrophils or monocytes (2 × 105 cells in IMDM/20% FCS), or unlabeled CD34+ cells (8 × 104 cells in IMDM/20% FCS) to each well. After an incubation of 60 minutes at 37°C, unattached cells were removed by three gentle washes of 300 µL exchanges of medium. Plates were checked by microscopy to ensure that there was no disruption of the endothelial monolayers. Adherent leukocytes were recovered by detergent lysis of the endothelium and adherent cells, and the associated cell counts were expressed as a percentage of the counts initially added to the wells. For quantification of progenitor cell adhesion nonadherent cells were counted and set up in clonogenic assays. Percentage adhesion of clonogenic cells was calculated from the clonogenic output of the cell suspension initially placed in the wells. For migration experiments, confluent endothelial monolayers on Transwell filters were washed three times with warm medium and placed in wells with fresh medium (IMDM/20% FCS). Labeled leukocytes, or CD34+ cells (8 × 105 cells per filter), were placed in the upper chamber and incubated for times as stated at 37°C in 5% CO2 in a humidified chamber. At the end of the experiment, transmigrated cells were recovered from the lower compartment. For leukocytes, percent migration was calculated from the associated counts, whereas transmigrated CD34+ cells were manually counted and set up in clonogenic assays. Percentage migration of clonogenic cells was calculated from the clonogenic output of the CD34+ cell suspension originally seeded onto the filters.Growth Factor Stimulation CD34+ cells were stimulated with IL-3 (12 ng/mL), SCF (10 ng/mL), and IL-6 (10 ng/mL) in IMDM/20% FCS for up to 5 days. Cells were harvested at varying time points, washed, and resuspended in fresh medium for phenotyping, adhesion, and transmigration assays as well as for cell cycle analysis.Cell Cycle Analysis Five to 10 × 105 cells were pelleted in a 15-mL tube and fixed in ice-cold 70% ethanol. Two-color flow cytometry of DNA (stained with propidium iodide [PI]) and total cell protein (stained with FITC) was performed as previously described.25 Analysis was carried out using an Epics-Elite flow cytometer (Coulter Electronics, Louton, UK).3H-Thymidine Suicide Assay Proliferation of CFCs was assessed with a 3H-thymidine suicide assay, which was adapted from previously described methods.14,26 Briefly, growth factor-stimulated cells were washed twice in serum-free IMDM before being divided into two equal aliquots of 1 to 3 × 106 cells (at 1 × 106 cells/mL). Test cells were incubated with 20 µL/mL of 3H-thymidine, whereas control cells were incubated with 20 µL/mL of 3H-thymidine together with excess cold thymidine (400 µg/mL), for 20 minutes at 37°C. Both aliquots of cells were subsequently washed twice with 10 mL each of IMDM containing 400 µg/mL of thymidine before being resuspended in IMDM/20%FCS for transmigration assays. Percent migration of clonogenic cells was quantified as described previously with clonogenic cultures set up for input and transmigrated cells in both the 3H-thymidine-treated and control samples. The contribution of nonproliferating CFCs to the migration in control cells was calculated from the percent migration in 3H-thymidine-treated (ie, nonproliferating) cells and subtracted from the overall migration in the control to give the actual contribution of proliferating CFCs to the overall transmigration in the control. This contribution was then expressed as percent migration of proliferating CFCs (number killed by 3H-thymidine suicide assay).Statistics Results are expressed as the mean ± standard error of the mean (SEM). Data were compared by using Student's t-test and a P value of <.05 was considered significant.
Adhesion of Primitive and Mature Cells to Endothelium The CFCs within the population of freshly isolated mobilized CD34+ cells showed significant levels of adhesion to unstimulated HUVECs (32% ± 3% for GM-CFCs, n = 12; and 35% ± 6% for BFU-E, n = 3) over a 1-hour incubation period (Fig 1A). These levels are comparable with those seen in peripheral blood monocytes (24.3% ± 2.2%). In comparison, neutrophils showed much lower levels of adhesion (5.6% ± 1.0%). Clonogenic cells adhered to both forms of endothelium (BMECs and HUVECs). There was no significant difference in adhesion between these two types of endothelium (Fig 1B).
Transmigration of Primitive and Mature Cells Across Endothelium The time taken for any cell type to traverse endothelium to any significant extent depends a great deal on the type of cell under study and the conditions of activation. CFCs in freshly isolated mobilized CD34+ cells showed very low levels of migration with only 1.0% ± 0.3% (n = 6) and 1.1% ± 0.6% (n = 3) of GM-CFCs migrating across unstimulated HUVECs and BMECs, respectively, over 20 hours (Figs 2 and 4D). In contrast, neutrophils and monocytes showed significant levels of transmigration over 2 hours and lymphocytes were able to transmigrate over 20 hours (Fig 2). We did not extend transmigration experiments beyond 20 hours, because there was progressive loss of barrier function of the endothelial monolayer after this time. The low levels of CFC migration contrasted with the high degree of adhesiveness of these cells.
Comparison of Bone Marrow and Peripheral Blood CD34+ Cells Harvested Simultaneously During G-CSF Mobilization in Transmigration Experiments In three patients undergoing G-CSF mobilization, bone marrow and peripheral blood progenitors were harvested simultaneously and set up in transmigration experiments using HUVECs. As seen in Table 1, there was no detectable difference between bone marrow and peripheral blood progenitors, both displaying very low levels of migration across endothelium.
Cell-Cycle Analysis of CD34+-Selected Cells and the Effect of Stimulation by Growth Factors We performed cell cycle analysis on mobilized, CD34+ cells by using PI staining. Greater than 95% of freshly isolated CD34+ cells are in G0/G1 of the cell cycle (Fig 3). After incubation with growth factors (IL-3 12 ng/mL, IL-6 10 ng/mL, and SCF 10 ng/mL) for 3 days, 28% ± 5% of cells (n = 6) are in S/G2/M (Fig 3). Using this growth factor combination, >90% of cells remain positive for CD34 with high levels of expression maintained at up to 4 days of stimulation (data not shown).
Effect of Growth Factor Stimulation on Adhesion and Transmigration of CD34+ Cells Short-term exposure to cytokines has been reported to increase adhesion of HPCs,27 an effect that might alter the transmigratory properties of these cells. Thus, we examined the transmigration of CFCs over 24 hours after cytokine addition. We used the cytokine combination of IL-3/IL-6/SCF as detailed previously. In these experiments, the transmigration of cytokine-treated GM-CFCs was 0.4% ± 0.2%, whereas that of untreated GM-CFCs was 0.6% ± 0.3% (the corresponding data for all CFCs being 0.5% ± 0.3% and 1.0% ± 0.5%, respectively), suggesting that short-term stimulation with cytokines does not alter transmigration of clonogenic CD34+ cells. We then proceeded to examine the effect of growth factor stimulation on adhesion and transmigration after 3 days of stimulation with IL-3, IL-6, and SCF. There is little difference in adhesion between freshly isolated and growth factor-activated CFCs (Fig 4A). In contrast, 3 days of stimulation with growth factors leads to a marked enhancement in the transmigration of clonogenic cells across HUVECs (9.8% ± 1.6% for GM-CFCs, P < .01; and 5.3% ± 1.2% for BFU-E, P < .05; n = 16 for both; Fig 4B). Differentiation of hematopoietic cells may be expected to lead to increased migratory capacity; however, the use of clonogenic assays helps to ensure that the cells being studied are at a similar level of differentiation.Effect of Growth Factor Stimulation on Expression of Adhesion Molecules on CD34+ Cells Enhanced transmigration after growth factor stimulation may relate to changes in surface adhesive phenotype. To address this issue, we examined CD34+-selected cells for surface expression of adhesion molecules before and after 3 days of exposure to growth factors. All samples were double stained with anti-CD34, and gates were set on CD34high side scatterlow cells. The vast majority of freshly isolated, peripheral blood-derived CD34+-selected cells express VLA-4 and PECAM-1 (CD31), whereas expression of LFA-1, L-selectin, and ICAM-1 was characterized by more individual variability (Table 2). Growth factor stimulation did not lead to any consistent change in expression of adhesion molecules with perhaps the exception of LFA-1, which, in three out of five patients studied, was expressed at low levels on unstimulated cells and was markedly upregulated after growth factor stimulation. The data for individual patients is given in Fig 5.
Proliferating CFCs Preferentially Migrate Across Endothelium The upregulation of migratory ability coincided with the onset of cell proliferation. To explore further the possible association between cell proliferation and cell transmigration, we used the 3H-thymidine suicide assay to eliminate actively proliferating cells and performed transmigration assays on the remaining nonproliferating population. Control cells were incubated with 3H-thymidine but in the presence of excess unlabeled thymidine. Treatment of growth factor-activated cells with 3H-thymidine led to 35.0% ± 6.9% loss of CFCs as determined by clonogenic assays. The elimination of proliferating cells by using 3H-thymidine led to a dramatic reduction in transmigration of CFCs. To determine the separate contribution of proliferating versus nonproliferating cells to the enhanced transmigration of growth factor-activated CFCs we calculated percent transmigration for each of these populations separately (see Materials and Methods). In this series of experiments, actively proliferating CFCs showed 11.7% ± 3.3% transmigration, whereas nonproliferating CFCs showed 1.3% ± 0.3% transmigration (P < .05, n = 5, Fig 6).
CD31 (PECAM-1) Is Required for the Transmigration of CD34+ Cells CD31 (PECAM-1) is a member of the Ig superfamily and has been identified as playing a role in transendothelial migration without mediating cell adhesion to endothelium.28 CD34+ cells express high levels of PECAM-1,5 with little difference between freshly isolated and growth factor-activated cells (Table 2). Experiments using neutrophils established that optimal inhibition of migration could be achieved with preincubating just the endothelial cells with blocking MoAb. Preincubation of HUVECs with anti-CD31 MoAb (10 µg/mL) produced marked inhibition of transmigration (70.8% ± 7.1% inhibition of GM-CFC transmigration; P < .05, n = 3). Adhesion of clonogenic cells was not inhibited by anti-CD31 (Fig 7). In contrast, anti-CD18 MoAb is able to inhibit both adhesion and transmigration (Fig 7), suggesting that this receptor is not specific for transmigration. In view of the increase in LFA-1 expression in three out of five patients studied, we tested the effect of anti-LFA-1 MoAb on transmigration of CD34+ cells. In two experiments, this MoAb (10 µg/mL) produced 81% and 51% inhibition of transmigration of GM-CFCs across HUVECs.
Differential Regulation of the Transmigration of CD34+ Cells and Peripheral Blood Neutrophils by IL-1 Stimulation of endothelium with cytokines such as IL-1 increases expression of adhesion receptors and the production of chemokines, thus leading to significant increase in the transmigration of inflammatory cells, including neutrophils and monocytes. Figure 8 shows that, after stimulation with IL-1 (10 U/mL for 4 hours), neutrophil transmigration is increased from 3.7% ± 0.3% to 38% ± 4.2% (P < .0001, n = 6). In contrast, IL-1 stimulation (20 U/mL for up to 18 hours) had no effect on the transmigration of unstimulated CFCs and minimal effect on the transmigration of cytokine-activated CFCs (Fig 8).
The main findings reported here are that, unlike their mature counterparts, and despite being highly adhesive, quiescent HPCs are unable to diapedese across endothelium, unless activated by growth factors. This dependence on growth factor activation applies to migration across both microvascular BMECs, as well as the more undifferentiated HUVECs. Growth factor stimulation leads to cell proliferation as well as increased migration. Elimination of proliferating CFCs by 3H-thymidine suicide assay results in marked reduction of transmigration in growth factor-activated cells, suggesting that proliferating CFCs migrate more efficiently than nonproliferating CFCs. The transmigration assay used in these studies takes into account the gross maturational effect of growth factor stimulation because, rather than measuring total cell migration, the assay quantifies clonogenic cells that are at similar levels of differentiation. We cannot conclude from these studies that cell cycling is a prerequisite for HPC homing/mobilization as subtle changes in activation status and maturational stage may have occurred in conjunction with entry into cell cycle. Cells measured in clonogenic assays are heterogenous and it is possible that after initial cytokine stimulation, there is a difference in growth factor requirements in the in vitro colony assays, which could influence the assessment of CFC migration. Although we cannot exclude this possibility, we have used multiple cytokine stimulation in the colony assays to minimize this problem. Initial studies of bone marrow CD34+ cells in three patients undergoing PBSC mobilization indicate that levels of transmigration are equally low in bone marrow-derived CFCs despite the fact that a proportion are known to be in cycle. This observation is unexplained but would support the notion that the link between proliferation and migration is not a direct causal one.
Submitted April 2, 1997;
accepted October 6, 1997.
We thank Dr John Sweetenham and Lisa Masek, Medical Oncology Unit, Southampton Hospital, UK for help with the isolation and culture of bone marrow endothelial cells. We also thank Dr John Harlan and Dr P. Newman for generous provision of antibodies.
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| Copyright © 1998 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Abstract
Introduction
Abstract
4-containing integrins, which mediate the initial
engagement of rolling cells. By analogy, the particular adhesion
molecule phenotype of HPCs might allow specific receptor/ligand
recognition events to occur between these cells and the lumenal surface
of bone marrow sinusoidal endothelium. HPCs have been shown to express
several adhesion molecules including lymphocyte function-associated-1
(LFA-1), very late activation antigen-4 (VLA-4), VLA-5, LFA-3,
L-selectin, Sialyl Lewisx(SLex), CD44,
intracellular adhesion molecule-1 (ICAM-1), and platelet endothelial
cell adhesion molecule-1 (PECAM-1).
1 integrin binding to fibronectin,
