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HEMATOPOIESIS
From the University of Washington, Seattle.
The specific retention of intravenously administered hemopoietic
cells within bone marrow is a complex multistep process. Despite recent
insights, the molecular mechanics governing this process remain largely
undefined. This study explored the influence of
Restriction of the developing hemopoietic cells to
certain anatomic sites within the body, that is, the extravascular
spaces of the bone marrow (BM), signifies a unique microenvironment
capable of providing not only anchorage to hemopoietic cells, but of
transmitting signals enabling their proliferation and differentiation.
The relationship of hemopoietic cells with their microenvironment is a
highly dynamic one allowing further expansion on demand and, depending
on the stimuli, the movement of cells in and out of their
microenvironment. The ability of intravenously administered cells to
re-establish connections within the BM environment is a clinically
exploited example of that flexibility. As the sinusoidal endothelial
cells separate the extravascular space from the circulation, intravenously administered cells need first to tether to the sinusoidal endothelium, then to firmly anchor themselves within the extravascular space through reversible adhesion and transmigration steps. Although several insights regarding the molecular pathways that guide these processes have been obtained, our knowledge of this complex process remains incomplete. Early reports suggest that galactose- and mannose-specific lectins (present on hemopoietic cells) interacting with counterreceptors in the marrow environment is important for successful engraftment.1 Subsequent reports demonstrate
that homing could be inhibited by several different molecular pathways using in vivo homing assays.2-6 For example, E- and
P-endothelial selectins, which are absent in the E- and P-deficient
mice, were found to be important for early stages of homing, providing
tethering and rolling of the cells on the BM
microvessels.4,5 Although a parallel contribution in
homing by the very late activation antigen-4/vascular cell adhesion
molecule-1 (VLA-4/VCAM-1) pathway was noted in these animals, which
confirmed earlier studies on the function of the VLA-4/VCAM-1 pathway
on homing,3 it was felt that this pathway could not
operate in the absence of endothelial selectins. In addition to
endothelial selectins, the presence of CXCR-4 on hemopoietic cells
interacting with its ligand stromal cell-derived factor-1 (SDF-1)
present on BM stroma and endothelial cells was deemed important in the
homing and engraftment of human hemopoietic cells in xenogeneic
hosts.6 Although the influence of SDF-1 on the maintenance
of hemopoiesis within BM and its chemotactic effects on hemopoietic
progenitor cells are undisputed,7-12 the impact of this
pathway in the early stages of homing has been called into question, at
least for murine cells.13-16 Follow-up studies by 2 groups
in the homing of fetal liver CXCR4 As previous homing studies with selectin-deficient recipients
suggested,4,5 the homing of hemopoietic cells to BM could follow the paradigm of mature leukocytes migrating to inflammatory tissues.22 Because Mice
Antibodies
Homing assays For homing studies, single-cell suspensions of BM donor cells prepared from the femurs/tibias of donor animals were washed, counted, and plated in quadruplicate in semisolid media to assess the number of clonogenic progenitors. A chosen inoculum of BM nucleated cells was injected via tail vein into lethally irradiated (1000-1200 R) recipients within 1 to 3 hours after irradiation. At various times after injection of donor cells (3 hours, 24 hours, 48 hours, 72 hours, 8 days, or 12 days), the animals were killed under anesthesia and circulating blood and selected tissues were obtained. Single-cell suspensions were prepared and counted to determine total cell numbers per organ, and an inoculum was cultured to determine the number of clonogenic donor cells present in each tissue. For calculating total BM, one femur was estimated to represent 6.7% of total BM, according to previous studies29 and values are expressed ± SEM. Cell suspensions from peripheral blood or other tissues were plated in duplicate or quadruplicate plates. In some experiments, nucleated donor cells were fluorescently labeled with carboxymethylfluorescein diacetate succinimidyl ester (CFSE, Molecular Probes, Eugene, OR), and in these experiments fluorescent cells were assessed at various times after transplantation (3 hours, 24 hours), using a FACSCalibur (Becton Dickinson, San Jose, CA) for analysis. A minimum of 1 × 105 nucleated cells was analyzed and calculations of total fluorescent cells recovered per organ were done, as stated above for culture colony-forming units (CFU-Cs).Assay for spleen colony-forming units, day 12 Primary recipient mice were irradiated with 1000 to 1200 cGy from a cesium source (at the dose rate of >100 cGy/min) and then injected intravenously with washed nucleated BM cells by tail vein. Mice were killed 12 to 14 days later, their spleens placed in Bouin fixative, transferred to 10% neutral buffered formalin, and the number of macroscopically visible spleen colonies counted under a dissecting microscope.CFU-C assays The presence of clonogenic progenitors (CFU-Cs) in donor BM cells or cells retrieved from the BM, peripheral blood, or spleen of irradiated recipients was determined by plating appropriate aliquots of test cells in methylcellulose in Iscoves modified Dulbecco medium supplemented with the following: 10% murine interleukin-3 (IL-3), (Collaborative Biomedical Products, Bedford, MA), 100 ng/mL murine stem cell factor (SCF; Peprotech, Rocky Hill, NJ), 5 U/mL human erythropoietin (Amgen, Thousand Oaks, CA), 5% pokeweed mitogen spleen cell conditioned medium, 10 4 M 2-mercaptoethanol, 30%
fetal bovine serum (FBS; Hyclone, Logan, UT), and 1% bovine serum
albumin (BSA; Intergen, Purchase, NY). Donor BM cells used for
transplantation were cultured at 1 × 105/mL, whereas
recipient BM cells early after transplantation (3 hours, 24 hours) were
cultured at 10 to 20 × 105/mL. After 7 to 9 days of
incubation at 37°C, 5% C02, and high humidity,
erythroid, granulocytic, or multilineage colonies were scored under a
dissecting microscope on the basis of their characteristic appearance
and color.
Immunofluorescent assays Single-cell suspensions from BM cells were lysed with hypotonic buffer and labeled with CFSE (Molecular Probes) at a final concentration of 0.5 µM (50 mM stock solution was prepared in dimethyl sulfoxide). Cells were incubated at 37°C for 10 minutes and the uptake of CFSE was terminated by adding cold Hanks balanced salt solution (HBSS) containing 5% FBS. The cells were subsequently washed twice in HBSS plus 5% FBS and resuspended in suitable concentrations for analysis or for injection. Recipient mice were injected with 20 × 106 cells to test the presence of CFSE-labeled donor cells lodged in BM or spleen, or present in peripheral blood of recipient animals. Cell suspensions from these tissues obtained 3 to 24 hours later were lysed to remove red cells, washed twice in phosphate-buffered saline (PBS) plus 5% FBS, and analyzed for the presence of fluorescent cells on a Becton Dickinson FACSCalibur, equipped with an argon ion laser set to 488 nm. Between 20 000 and 100 000 ungated events were collected to obtain a measure of the proportion of cells positive for CFSE. The total number of CFSE+ cells in any given organ from which the sample was taken was calculated by multiplying the proportion of CFSE+ cells by the total number of nucleated cells recovered per organ. At the same time, an aliquot of cells was cultured to enumerate CFU-Cs present within the BM cell suspension. In certain experiments the proportion of CD18+, or that of L-selectin-positive cells was determined in recipient animals. For this purpose, either whole blood or cell suspensions from the BM or cells retrieved from in vitro colonies were labeled with the fluorescent-conjugated antibody (1 µg/106 cells for 40 minutes at 4°C), washed, and subsequently analyzed on the FACSCalibur.Statistics Statistical analysis was performed using Student t test as found in Microsoft Excel software, using 2-tailed analysis assuming unequal sample variance.
CD18  2-integrins in homing we
initiated our experiments using cells treated with antifunctional
antibodies. Cells treated with either anti-CD18 (clone 2E6) or
anti-CD11a (LFA-1) (clone 17/4) antibodies did not differ from
untreated control cells in terms of their ability to lodge to BM or
spleen. Lodgment in the BM at 3 hours of anti-CD18-treated cells was
at 120% ± 11.0% of control levels (P = .133), whereas
lodgment of anti-CD11a-treated cells was at 77% ± 17.0%
(P = .181). Inhibition of homing with antibodies used in
vitro has not always been confirmed with gene-targeted mice (eg,
studies with anti-CD44),19 so when CD18-deficient animals
became available, we tested CD18-deficient cells in homing. In 2 separate experiments, no differences were found in the homing patterns
at 3 hours between normal (CD18+/+) BM cells and
CD18/ cells, both given to normal (CD18+/+)
littermate recipients (Figure 1). To
explore whether the kinetics of homing were different between
CD18/ and CD18+/+ cells, we also determined
homing values at 24 hours. Again, as seen in Figure 1, the patterns of
normal and deficient cells were not statistically different. A small
tendency for more CD18/ CFU-Cs to be present in
peripheral blood was seen, but the differences were not statistically
significant (P  .05). In addition to CD18 null mice we
also tested intercellular adhesion molecule-1 (ICAM-1)-deficient mice
as recipients. (ICAM-1 is the major endothelial ligand of leukocyte
function-associated antigen [LFA-1].) Whether CD18+/+
cells or CD18/ cells were given in these animals, there
were no homing defects. (BM seeding of double-positive cells to
double-positive recipients: 10.09% ± 1.48%; to
ICAM-1/ recipients: 9.64% ± 0.87%.
ICAM-1/ recipients given CD18/ cells:
17.5% ± 1.8%. There were 5 animals in each group.)
CD18 / cells proliferated to the same extent as control
CD18+/+ cells, we measured the CFU-C content of BM at 8, 14, or 43 days after transplantation. As seen in Table
1, reconstitution of hemopoiesis, using
BM or peripheral blood values, was comparable to controls. To confirm
that reconstitution did occur with CD18/ cells, BM
cells from these recipients, as well as colony-derived cells from
cultured BM samples were labeled with anti-CD18. As seen in Figure
2, the great majority of cells
repopulating these recipients were CD18/ negative. It
is of note that in the earlier experiments (8-day data in Table 1) we
encountered problems with sick animals or contaminated cultures.
Because of this, all subsequent experiments were carried out with
antibiotic-pretreated CD18/ donors.
The above data appear to be in stark contrast to the prominent defects
seen in mature leukocyte adhesion in mice with
Homing in triple selectin-deficient recipients
(EPL / animals into irradiated
EPL/ recipients or double-positive recipient animals
(B6.129) and compared results to recipient animals of either kind given
double-positive cells. Data from all the above donor/recipient
combinations are illustrated in Figure 3.
BM homing at 3 hours measured as percent of clonogenic cells injected
was similar when double-negative cells were used in double-positive,
EPL/, or EP/ recipients (Figure 3).
Homing was also evaluated at 24 and 72 hours when double-positive cells
were given to EPL/ recipients or at 48 hours when
double-negative cells (from EPL/ mice) were given to
EPL/ recipients (Figure 3). Again, we failed to detect
statistically significant differences in all combinations. In view of
the divergence of our results to those published before,5
we tested the survival of EPL/ mice that received
transplants of double-positive cells, as it was done previously. As
seen in Figure 4, all
EPL/ animals that received transplants of
5 × 104 cells died, in contrast to controls, thus
confirming the prior data.5 However, it was noted that
animals that died in the prior study5 had 10 times more
neutrophils in their blood compared to controls that survived. It was
suspected that these animals may have succumbed to infectious
complications rather than to graft failure. This speculation was
reinforced by the fact that we were confronted with many contaminated
cultures. For this reason, in all subsequent experiments,
selectin-deficient animals used as recipients were treated with
antibiotics for at least a week prior to their irradiation. When spleen
colony-forming units (CFU-Ss) were evaluated in the spleens of
recipient animals 2 weeks after transplantation and their BM
proliferative activity was assessed, we found that the BM cellularity
was higher in EPL/ recipients, but the total contents
of CFU-Cs in BM or CFU-Ss in spleen were similar to controls (Table
2). To test whether the proliferative
activity was derived from selectin-deficient cells, we labeled BM cells
with anti-L-selectin antibodies and compared the percent positivity in
recipients of double-positive or double-negative cells. As seen in
Figure 2, virtually all repopulation activity in double-positive
recipients of EPL/ donor cells was by the
double-negative donor cells up to 30 days after transplantation.
Taken together, our data with EP Homing patterns of CD18 / cells showed indistinguishable
patterns from normal cells in their homing at 3, 24, and 48 hours, we
wondered whether the same could be true when selectin-deficient animals were used as recipients, or that the combination of 2-
integrin-deficient cells given to selectin-deficient recipients could
have a compounding homing defect. For this reason,
CD18/ BM cells were injected into irradiated
EP/ recipients. The results of these experiments are
shown in Figure 5. No differences between
CD18/ cells given to normal recipients versus
EP/ recipients were uncovered.
The combination of When mature cells were examined in vitro, the compound CD18 and
E-selectin deficiency provided the most severe defect on their rolling
and adhesion in all assays tested.30 In view of these defects of mature cells, several possibilities can be considered to
explain our data with normal homing of doubly deficient stem/progenitor cells. It has been previously stated that rolling, even in mature cells, should be affected by over 90% to influence
adhesion.41 Thus, in the special hemodynamics of BM
vasculature, either firm adhesion and transmigration phenomena are not
measurably affected by decreased rolling, or the latter can be
substituted by alternate adhesion pathways. The picture is reminiscent
of the selectin-independent accumulation of neutrophils in lung or
liver vasculature23 and our results with superimposed
abrogation of Observations in hypomorphic (D4D) VCAM-1 mice We have previously shown that the specific retention of intravenously administered BM cells to the BM is mediated partly by the VLA-4/VCAM-1 pathway.3 This conclusion was based on the use of antifunctional antibodies, either against VLA-4 or VCAM-1. Subsequent studies have confirmed this observation4,17 using the same or different approaches. Observations in gene-targeting mice have conclusively shown the importance of1-integrins in colonization of hemopoietic sites in
development and in postnatal life (fetal liver, BM, spleen). However,
the specific partnership of  4 with 1 in
this effect has not been confirmed,21 despite the
demonstrated importance of 4 in the maintenance of
normal hematopoiesis.42,43 To expand on these
observations, we have used hypomorphic VCAM-1 mice with D4D and low
expression (about 5%) of VCAM-1 (Figure
6B). The 4-integrin binds
to the homologous domains 1 and 4 of VCAM-1. Domain 1 appears to be
primarily responsible for 4/VCAM-1-dependent primary
capture of mature cells under flow, but both domain 1 and domain 4 can
be used for adhesion under static conditions.44-46
Therefore, D4D mice with low total expression of domain 1 containing
protein provide an opportunity, albeit imperfect, to test the
physiologic relevance of observations with antibodies. We have
generated a small number of animals by breeding heterozygote pairs. We
noted that in these animals, both the baseline presence of CFU-Cs and
CFU-Ss in the blood is higher than the controls (Figure 6). Also, when
these mice were used as recipients for homing experiments, reduction in
homing was seen and was virtually abrogated when the animals were
treated with MK2 antibody (which binds to domain 1 of
VCAM-132) and were given anti-CD11a-treated cells (Figure
6). These observations appear to be consistent with a role of VCAM-1 in
the trafficking and homing of hemopoietic progenitors.
Combined antibody treatments or combination of deficiencies Because the inhibition of homing by anti-VLA-4 is partial, we wanted to test to what extent the combination of anti-4
and anti-2-integrin antibodies or the injection of
anti-4-treated cells into selectin-deficient animals
could compound homing defects. It is of interest that single treatment
with antibodies to 2-integrins (anti-CD18 or anti-CD11a,
data presented herein) or antibodies against L-selectin4,17
did not inhibit homing. However, addition of anti-4 to
other antibody treatments elicits an inhibition that was over 90% to
that of untreated or single antibody-treated cells (Figure
7). The same magnitude of inhibition was
also seen with 3 antibodies (to 62L + 18 + 49d) or with a
combination of anti-VCAM-1 treatment of recipients and anti-LFA-1
treatment of donor cells in D4D mice (Figure 6). We then treated
CD18-deficient (CD18 hypomorphic or CD18/) or
selectin-deficient cells with anti-4 and assessed their homing, either in EPL/ recipients as compared to
double-positive recipients. As seen in Figure 7, the results of
synergistic inhibition of homing obtained with combined antibody
treatments were largely confirmed when cells from CD18-deficient
animals were treated with anti-4 antibody. For
complementary evidence we ascertained the homing patterns of
CD18/ cells using both the CFSE- labeling approach used
previously,19,32 a direct approach not dependent on
proliferative potential, and our CFU-C approach within the same
experiment. CFSE-stained CD18/ BMs were injected
(untreated or treated with anti-4 antibody) into normal
recipients, which were killed for analysis at 24 and 72 hours. Figure
8 shows the recovery of CFSE-labeled
cells analyzed by FACS from the BM and peripheral blood of recipients.
The same samples were also assessed for CFU-C recovery by clonogenic
assays. Homing to BM by the functional CFU-C assay at 24 hours was
6.0% ± 0.85%, well within the range previously observed (Figure 1) and with anti-4-treated cells was 0.2% ± 0.096%.
Respective values for CFSE-labeled cells were 16.04% ± 0.87% without
anti-4 and 0.98% ± 0.36% with anti-4
treatment. At 72 hours, BM CFU-C recovery was 22.7% ± 1.58% of
injected and 0.37% ± 0.067% for anti-4-treated cells. CFSE evaluation at 72 hours showed values well below the 24-hour
ones for both sets of transplanted CFSE cells (data not shown). The
above data and data with anti-4-treated cells from EPL/ animals given to EPL/ recipients
(Figure 7), collectively point to a dominant effect of 4
with a synergistic contribution by 2-integrins and
selectins in the initial capture of cells in BM whenever function of
4 is compromised.
According to earlier descriptions of the adhesion cascade
governing the migration of mature leukocytes to inflammatory sites, integrins did not participate in the first stages of rolling and tethering to the activated endothelium.22 Multiple recent
examples have shown that There are several reasons to suggest that the All versatile functions of Of interest, the VCAM-1-dependent retention of B cells in BM65,66 resembles data with CXCR4/SDF-1 mice69 and CD24-deficient mice.70 It is tempting to speculate that VCAM-1 may serve as a common mechanistic pathway mediating the action of other pathways in homing, such as SDF-1/CXCR4.69,71,72 Recent data73 showing that, in the absence of selectins, immobilized SDF-1 promoted VLA-4-mediated tethering and firm adhesion of human CD34+ cells to VCAM-1 under shear flow in vitro, provide an additional scenario reinforcing views presented herein about the mechanics of homing.
We are indebted to Drs A. Beaudet and M. Cybulsky for the generous supply of their mice, and Drs Roy Lobb and R. Winn for the supply of antibodies. We thank Domino Hawks for her expert secretarial assistance.
Submitted April 16, 2001; accepted June 22, 2001.
Supported by National Institutes of Health grants HL58734 and AI32177.
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.
Reprints: Thalia Papayannopoulou, Division of Hematology, University of Washington, Box 357710, Seattle, WA 98195-7710; e-mail: thalp{at}u.washington.edu.
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H. Takizawa, C. Kubo-Akashi, I. Nobuhisa, S.-M. Kwon, M. Iseki, T. Taga, K. Takatsu, and S. Takaki Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk Blood, April 1, 2006; 107(7): 2968 - 2975. [Abstract] [Full Text] [PDF]
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T. Ulyanova, L. M. Scott, G. V. Priestley, Y. Jiang, B. Nakamoto, P. A. Koni, and T. Papayannopoulou VCAM-1 expression in adult hematopoietic and nonhematopoietic cells is controlled by tissue-inductive signals and reflects their developmental origin Blood, July 1, 2005; 106(1): 86 - 94. [Abstract] [Full Text] [PDF]
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A. Hidalgo and P. S. Frenette Enforced fucosylation of neonatal CD34+ cells generates selectin ligands that enhance the initial interactions with microvessels but not homing to bone marrow Blood, January 15, 2005; 105(2): 567 - 575. [Abstract] [Full Text] [PDF]
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E. Chavakis, A. Aicher, C. Heeschen, K.-i. Sasaki, R. Kaiser, N. El Makhfi, C. Urbich, T. Peters, K. Scharffetter-Kochanek, A. M. Zeiher, et al. Role of {beta}2-integrins for homing and neovascularization capacity of endothelial progenitor cells J. Exp. Med., January 3, 2005; 201(1): 63 - 72. [Abstract] [Full Text] [PDF]
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Y. Katayama, A. Hidalgo, B. C. Furie, D. Vestweber, B. Furie, and P. S. Frenette PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and {alpha}4 integrin Blood, September 15, 2003; 102(6): 2060 - 2067. [Abstract] [Full Text] [PDF]
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F. Bertolini, S. Paul, P. Mancuso, S. Monestiroli, A. Gobbi, Y. Shaked, and R. S. Kerbel Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells Cancer Res., August 1, 2003; 63(15): 4342 - 4346. [Abstract] [Full Text] [PDF]
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T. Papayannopoulou, G. V. Priestley, H. Bonig, and B. Nakamoto The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization Blood, June 15, 2003; 101(12): 4739 - 4747. [Abstract] [Full Text] [PDF]
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Y.-C. Gu, J. Kortesmaa, K. Tryggvason, J. Persson, P. Ekblom, S.-E. Jacobsen, and M. Ekblom Laminin isoform-specific promotion of adhesion and migration of human bone marrow progenitor cells Blood, February 1, 2003; 101(3): 877 - 885. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
-irradiated mice.
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