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Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 952-958
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Expression of VEGFR-2 and AC133 by circulating human
CD34+ cells identifies a population of functional
endothelial precursors
Mario Peichev,
Afzal J. Naiyer,
Daniel Pereira,
Zhenping Zhu,
William J. Lane,
Mathew Williams,
Mehmet C. Oz,
Daniel J. Hicklin,
Larry Witte,
Malcolm A. S. Moore, and
Shahin Rafii
From the Division of Hematology-Oncology, Weill Medical College of
Cornell University, New York, NY; Division of Molecular, Cell Biology
and Immunology, ImClone Systems, New York, NY; Department of
Cardiothoracic Surgery, Columbia-Presbyterian Medical Center, New York,
NY; and Division of Developmental Hematopoiesis, Sloan Kettering Cancer
Center, New York, NY.
 |
Abstract |
Emerging data suggest that a subset of circulating human
CD34+ cells have phenotypic features of endothelial
cells. Whether these cells are sloughed mature endothelial cells or
functional circulating endothelial precursors (CEPs) is not known.
Using monoclonal antibodies (MoAbs) to the extracellular domain of the human vascular endothelial receptor-2 (VEGFR-2), we have shown that
1.2 ± 0.3% of CD34+ cells isolated from fetal liver
(FL), 2 ± 0.5% from mobilized peripheral blood, and 1.4 ± 0.5%
from cord blood were VEGFR-2+. In addition, most
CD34+VEGFR-2+ cells express hematopoietic
stem cell marker AC133. Because mature endothelial cells do not express
AC133, coexpression of VEGFR-2 and AC133 on CD34+ cells
phenotypically identifies a unique population of CEPs. CD34+VEGFR-2+ cells express
endothelial-specific markers, including VE-cadherin and E-selectin.
Also, virtually all CD34+VEGFR-2+ cells
express the chemokine receptor CXCR4 and migrate in response to stromal-derived factor (SDF)-1 or VEGF. To quantitate the plating efficiency of CD34+ cells that give rise to endothelial
colonies, CD34+ cells derived from FL were incubated with
VEGF and fibroblast growth factor (FGF)-2. Subsequent isolation and
plating of nonadherent FL-derived VEGFR-2+ cells with
VEGF and FGF-2 resulted in differentiation of AC133+
VEGFR-2+ cells into adherent
AC133 VEGFR-2+Ac-LDL+
(acetylated low-density lipoprotein) colonies (plating
efficiency of 3%). In an in vivo human model, we have found that the
neo-intima formed on the surface of left ventricular assist devices
is colonized with AC133+VEGFR-2+ cells.
These data suggest that circulating CD34+ cells
expressing VEGFR-2 and AC133 constitute a phenotypically and
functionally distinct population of circulating endothelial cells that
may play a role in neo-angiogenesis.
(Blood. 2000;95:952-958)
© 2000 by The American Society of Hematology.
 |
Introduction |
Wound healing and tumor growth require active
endothelial proliferation, a process referred to as neo-angiogenesis.
Neo-angiogenesis involves the recruitment of endothelial cells to the
site of injury or to the tumor vascular bed. Two possible sources of
endothelialization are (1) endothelial migration and sprouting from
preexisting endothelial cells or (2) recruitment of endothelial
precursor cells from the circulation. There is ample evidence for the
first scenario. However, the existence of circulating endothelial
precursor (CEP) cells in adult humans has only recently been suggested
and is under intensive scrutiny.
Many studies have demonstrated the presence of mature circulating
endothelial cells in the peripheral circulation.1-6 Mature endothelial cells may appear in the circulation randomly by
shedding from the vascular wall. Trauma induced by surgery or increased intravascular turbulence may also result in the introduction of endothelial cells to the peripheral circulation. Patients with sickle cell crisis have been shown to have increased numbers of activated circulating endothelial cells.5 Although
circulating endothelial cells have been suspected to have the capacity
to colonize vascular grafts,1,4,6,7 the contribution of these cells to postnatal angiogenesis or vasculogenesis is not known.
Endothelial precursor cells have properties similar to those of
embryonic angioblasts, which can be defined as migratory endothelial cells with the capacity to circulate, proliferate, and differentiate into mature endothelial cells, but which have not yet acquired characteristic mature endothelial markers and have not yet formed a
lumen.8-10 Although there is plethora of evidence for the
existence of angioblasts during embryonic development, the existence of angioblast-like endothelial precursor cells in adult circulation has
been hampered by the absence of specific phenotypic markers and
functional assays to define this unique cell population.
Both endothelial precursor cells and mature endothelial cells may
express similar endothelial-specific markers, including vascular
endothelial growth factor receptor-2 (VEGFR-2),11
Tie-1,12,13 Tie-2,14 and vascular endothelial
(VE)-cadherin.15,16 Therefore, it may be impractical to use
these markers to differentiate between the 2 populations.
Identification of the differences between endothelial precursor cells
and circulating mature endothelial cells is further complicated by the
fact that hematopoietic stem and progenitor cells express markers
similar to those of endothelial cells, such as VEGFR-1 (Flt-1), CD34,
platelet endothelial cell adhesion molecule (PECAM), Tie-1, Tie-2, and
von Willebrand's factor (vWF), and they also have the capacity to
incorporate acetylated low-density lipoprotein
(Ac-LDL).
One study has shown that CD34+VEGFR-2+ cells
can be detected in the peripheral circulation.17 However,
in this report a polyclonal antibody to the intracellular domain of
VEGFR-2 was used to identify viable
Ac-LDL+CD34+ endothelial progenitor cells. This
may have resulted in the co-isolation and transplantation of
contaminating hematopoietic cells as well as endothelial cells. We have
shown that allogeneic sex-mismatched bone marrow transplantation
results in the transfer of endothelial cells to recipient
dogs.2 Replacement of the aorta of the recipient dogs
months after transplantation with impervious Dacron grafts resulted in graft endothelialization arising exclusively from the
transplanted bone marrow. In humans, similar evidence for endothelial
precursor cells originates from patients implanted with a left
ventricular assist device (LVAD). We demonstrated colonization of the
flow surface of the titanium housing of LVADs with CD34+
endothelial-like cells 6 months after the devices were
removed.1 However, none of these studies has conclusively
demonstrated the existence of a phenotypically and functionally
distinct population of CEPs.
Endothelial precursor cells may share similar characteristics with
hematopoietic stem cells. CD34+ hematopoietic stem cells
can be detected at low numbers in bone marrow, fetal liver, and
umbilical cord blood. Although the number of circulating hematopoietic
stem cells in the peripheral circulation is very low, cytokines such as
granulocyte colony-stimulating factor (G-CSF) promote mobilization of
stem cells from bone marrow to the peripheral blood (PB). In addition,
hematopoietic stem and progenitor cells express unique surface markers,
such as CD34 and the newly discovered early hematopoietic stem cell
marker AC133. Expression of CD34 and AC133 diminish with maturation and differentiation.18,19
AC133 is a novel 120-kd glycosylated polypeptide that contains
5-transmembrane domains with an extracellular N-terminus and a
cytoplasmic C-residue.18,19 The function of AC133, which does not share homology with any previously described hematopoietic cell surface antigen, is not known. However, isolation of a
subpopulation of CD34+ cells using
monoclonal antibody (MoAb) to human AC133 has resulted in the
identification of functional CD34+ population of
hematopoietic stem cells. Human-derived AC133+ cells can
repopulate sheep bone marrow19 and, therefore, can be
considered pluripotent hematopoietic stem cells. Expression of AC133 is
rapidly downregulated as hematopoietic progenitors and stem cells
differentiate into more mature postmitotic cells. In fact, virtually
all mature hematopoietic cells, including mature myeloid,
megakaryocytes, erythroid, and lymphoid cells and terminally differentiated hematopoietic cells, fail to express
AC133.18,19 Therefore, subsets of CD34+ cells
that express AC133 are truly a phenotypic and functional marker of an
immature population of hematopoietic stem and progenitor cells.
In search of unique endothelial markers to facilitate the isolation and
characterization of endothelial precursor cells, we have found that
AC133 is expressed on subset of CEPs but not on mature differentiated
endothelial cells. To examine the possibility that the
endothelial-specific marker VEGFR-2 may be expressed on subsets of
circulating AC133+ cells, we have used a combination of
high affinity to the extracellular domain of VEGFR-2 to identify CEPs.
In this paper, we demonstrate that a small subset of CD34+
cells derived from different hematopoietic sources express AC133 and
VEGFR-2. In addition, these cells express endothelial-specific antigens, including E-selectin and VE-cadherin. Almost all circulating VEGFR-2+ cells express the chemokine receptor CXCR-4 and
migrate in response to the CXCR-4 ligand, stromal-derived factor
(SDF-1), as well as VEGF. Incubation of nonadherent CD34+
cells coexpressing AC133 and VEGFR-2 cells with VEGF, fibroblast growth
factor (FGF)-2, and collagen results in their proliferation and
differentiation into adherent AC133
VEGFR-2+ mature endothelial cells. In a relevant in vivo
model, we demonstrate that the neo-intimal surface of LVADs is also
colonized with large numbers of AC133+VEGFR-2+
cells. Taken together, these results suggest that circulating CD34+ cells expressing VEGFR-2 and AC133 comprise
a functional population of CEPs cells that may play a
role in postnatal angiogenesis or vasculogenesis.
 |
Materials and methods |
Flow cytometry studies
CD34+ cells were isolated from cord blood (CB),
G-CSF-mobilized PB, and human fetal liver (FL) using standard
immunomagnetic techniques (MACS; Miltenyi Biotech,
Auburn, CA). Permission for obtaining the samples was obtained from the
Institutional Review Board.
For identification of VEGFR-2+ cells, CD34+
cells were incubated with 1.5 µL of FITC-labeled high-affinity,
nonneutralizing MoAbs to VEGFR-2 (clones 4.13 and 6.64; ImClone
Systems, New York, NY) and a phycoerythrin (PE; red
fluorescence)-labeled anti-CD34 antibody (Becton Dickinson, San Jose,
CA) for 20 minutes. The number of positive cells was compared to
immunoglobulin G isotype control (FITC; Immunotech, Marceille, France)
and determined using Coulter Elite flow cytometer (COULTER, Hialeah,
FL). Nonviable cells identified by propidium iodide staining and, also,
contaminating monocytes marked by expression of CD15 and CD14 were excluded.
In addition, different combinations of endothelial (EC)-specific
markers (PE-labeled), along with FITC-conjugated MoAb
directed to VEGFR-2, were used in dual-color flow cytometry for
quantification of CEP phenotype. EC-specific markers
included E-selectin (BioSource International, Camarillo,
CA, VE-cadherin (BV9 clone; ImClone Systems), and less
specific but common markers that are expressed on endothelial cells,
including PECAM (Becton Dickinson), vascular cell adhesion molecule
(VCAM)-1 (BioSource International, Camarillo, CA),
intercellular adhesion molecule (ICAM)-1 (Immunotech), CD13 (Immunotech), and CXCR-4 (clone 12G5; Pharmingen, San Diego, CA), the
chemokine receptor for SDF-1.
Migration studies
Migration of CD34+VEGFR-2+ cells was studied
by a modified in vitro transmigration assay. An enriched population of
CD34+ cells derived from mobilized PB at
105 cells per well (containing 2 × 103
CD34+VEGFR-2+ cells) was placed on the upper
chamber of a 5-micron-diameter bare Costar transwell plate (Modified
Boyden Chamber, Costar Corp, Cambridge, MA). Immediately, 200 ng/mL of
SDF-1 (Pepro Tech, Rocky Hill, NJ) were added to the lower chamber;
after 3 hours of incubation, the number of CD34+
VEGFR-2+ cells migrating to the lower chamber were
quantified by 2-color flow cytometry. AC133 staining was done with a
PE-conjugated antibody (Miltenyi Biotech) as described above. Human
umbilical vein endothelial cells (HUVEC), used as a control for the
presence of AC133, were isolated as described previously.22
To test the ability of CD34+VEGFR-2+ cells to
migrate in response to VEGF, 105 CD34+ cells
were placed in the upper chamber of a 5-micron Costar transwell plate,
and immediately VEGF165 (Pepro Tech) 100 ng/mL was added to
the lower chamber. CD34+VEGFR-2+ cells
migrating to the lower chamber were quantified with 2-color flow cytometry.
Endothelial colony assay
Freshly isolated CD34+ cells were analyzed for the
presence of AC133+VEGFR-2+ cells. Subsequently,
106 CD34+ cells were incubated in EC media
containing medium 199 (M199; GIBCO-BRL, Gaithersburg, MD) supplemented
with 20% fetal bovine serum (HY CLONE, UT), FGF-2 5 ng/mL (human recombinant fibroblast growth factor-basic; SIGMA, St.
Louis, MO), and heparin 5 units/mL. After 3 days, nonadherent cells
were transferred to collagen-coated (1 µg/mL) plastic dishes and
grown in the same media for 2 weeks. This incubation resulted in
attachment and proliferation of CD34+ cells expressing
VEGFR-2 into monolayers of mature endothelial cells. Cells were stained
for endothelial-specific antigens, including vWF, VE-cadherin and,
after activation with interleukin (IL)-1 (10 units/mL), for
E-selectin expression. AC133 staining of the newly formed endothelium
was done using the protocol as described above.
CD34+ cells were purified from human FL (obtained at 14 to
16 weeks of gestation) using Miltenyi isolation technique. After isolation, CD34+ cells were analyzed for the presence of
VEGFR-2 and AC133 expression and incubated with the above EC media
containing FGF-2 and VEGF for 3 days.
Consequently, 3 × 106 nonadherent cells were
incubated with Biotin-labeled anti-VEGFR-2 (1 µg/mL clone 4.13;
ImClone Systems) and, after 30 minutes of mixing, washed and
reincubated with 160 µg of Strepavidin Dynabeads M-280 (DYNAL A.S.,
Oslo, Norway) for 45 minutes on bidirectional mixer at 4°C.
Rosetted cells were isolated using magnetic DYNAL MPC
and, after removal of the supernatant, the cells were washed and
incubated with EC media for 18 hours to allow for detachment of the
beads. A total of 100 cells released from the beads were plated on
collagen-coated dishes in EC-specific media using different dilutions:
1:2, 1:10, 1:20, 1:50, 1:100, and 1:200. After 10 to 14 days, the
number of EC colonies were quantified and analyzed using Dil-Ac-LDL
incorporation. Dil-Ac-LDL (1 µg/mL, Human Dil Acetyl-LDL; PerImmune,
Inc, Rockville, MD) was added to the media for 4 hours, and EC-specific
metabolic labeling was assessed by visualization under Nikon-Diaphot
microscope with mercury lamp 20 × phase objective.
Identification of VEGFR-2+ cells from LVAD
neo-intima
Mononuclear cells from LVAD neo-intimal surfaces were obtained as
previously described.1 Briefly, after explantation of LVADs, the neo-intima covering the textured surface was removed, washed, and digested with 0.1% collagenase. Mononuclear cells were
recovered and washed, and the number of
CD34+VEGFR-2+ cells and
AC133+VEGFR-2+ cells was determined by
dual-color flow cytometry. A total of 6 LVADs were processed and
extracted cells analyzed for the presence of AC133+
VEGFR+ cells. Depending on the clinical
circumstances, the LVADs were explanted at different times, ranging
from 28 days to 6 months.
Statistical analysis
Data are expressed as mean ± SEM of at least 3 independent
experiments. To detect differences between migrating and nonmigrating cells, the t test for paired samples was applied. A P
value of <.05 was considered statistically significant.
 |
Results |
MoAbs to the VEGFR-2 identify a small subpopulation of circulating
CD34+ endothelial cells
To quantify the number of CD34+VEGFR-2+
cells within different hematopoietic sites, CD34+ cells
isolated from cytokine-mobilized PB, CB, and FL were analyzed for the
presence of CD34+ VEGFR-2+ cells by 2-color
flow cytometry. Using FITC-labeled MoAbs to the extracellular domain of
VEGFR-2, we found that 2.0 ± 0.5% (n = 5) of CD34+
cells derived from G-CSF mobilized PB, and 1.4 ± 0.5% (n = 3) of CB-derived CD34+ cells, and 1.2 ± 0.3% of
CD34+ isolated from FL (n = 3) were VEGFR-2+
(Figure 1). Similar
analysis of the frequency of CD34+VEGFR-2+
cells in nonmobilized PB showed a very small number of these cells
(data not shown). These results demonstrate the presence of small but
distinctive population of VEGFR-2+ cells within
CD34+ hematopoietic cells.

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| Fig 1.
Expression of VEGFR-2 on CD34+ cells from
different hematopoietic sources identifies a small subpopulation of
circulating endothelial cells.
Viable CD34+ cells, as shown by the typical fluorscence in
forward and side scatter (A), were isolated from cytokine-mobilized PB
(C), CB (D), and FL (E). Subsequently, the number of
CD34+VEGFR-2+ cells was analyzed by 2-color
flow cytometry using a combination of FITC-labeled
MoAbs to the extracellular domain of VEGFR-2 (clones
4.13 and 6.64) and PE-labeled MoAb directed to CD34.
X-axis represents log fluorescence intensity. Percentage of positive
cells was compared to isotype control (B).
|
|
AC133 is expressed on CEPs but not on mature endothelial cells.
VEGFR-2 is expected to be expressed on both mature circulating
endothelial cells and CEPs. Therefore, the
CD34+VEGFR-2+ cells identified in Figure 1 may
represent a heterogeneous population of mature and immature endothelial
cells. In this respect, we have searched for a specific marker that is
expressed on CEP but not on mature endothelial cells. We have found
that the most CD34+VEGFR-2+ cells express the
newly discovered hematopoietic stem cell marker AC133, which is also
present on immature hematopoietic cells but is absent on mature
endothelial or differentiated hematopoietic cells.
CD34+ cells isolated from different hematopoietic sources
were analyzed by 2-color flow cytometry using PE-conjugated MoAb to
AC133 and FITC-conjugated MoAb to VEGFR-2. Almost all of the VEGFR-2+ cells derived from mobilized PB that expressed
VEGFR-2 also coexpressed AC133 (Figure 2A).
However, although mature early-passage HUVECs expressed VEGFR-2, they
failed to express AC133 (Figure 2B, 2C). These data suggest that
CD34+ cells coexpressing VEGFR-2 and AC133 may represent a
phenotypically distinct population of CEPs. The frequency of
CD34+ cells expressing VEGFR-2 and AC133 in PB was only
0.4 ± 0.2% of the total CD34+ population (0.002% of
total mononuclear cells). However, with G-CSF mobilization there was an
increase in the number of AC133+VEGFR-2+ CEPs
to 2.0 ± 0.5% of the CD34+ cells (0.02% of total
mobilized mononuclear cells). CB- and FL-derived CD34+
cells contained 1.4 ± 0.5% and 1.2 ± 0.3%
AC133+VEGFR-2+ cells, respectively. The number
of AC133 CD34+VEGFR-2+ cells,
which most likely represent mature circulating endothelial cells,
composed a very small percentage of the circulating population in
mobilized blood. These data demonstrate the existence of low levels but
persistent numbers of circulating
AC133+VEGFR-2+ cells in various hematopoietic
sites.

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| Fig 2.
AC133, an early hematopoietic stem cell marker is
expressed on VEGFR-2+ CEPs but not on mature endothelial
cells.
CD34+ cells derived from mobilized peripheral blood (A) and
HUVEC monolayers were analyzed for the expression of AC133. Only the
circulating CD34+ VEGFR-2+ cells express AC133,
but not mature adherent HUVECs (B, C). CD34+ cells
coexpressing VEGFR-2 and AC133 were present in different hematopoietic
sources (D), with the highest percentage found in cytokine-mobilized
peripheral blood (2 ± 0.5%) and the lowest in unmobilized
peripheral blood (0.4 ± 0.2%). X-axis represents log
fluorescence intensity.
|
|
Phenotypic characteristics of putative circulating CEPs.
CD34+ cells isolated from various hematopoietic
microenvironments were analyzed for the presence of other hematopoietic
and endothelial markers. Using dual-color flow cytometry, we showed that human CD34+VEGFR-2+ cells express
endothelial-specific markers, including E-selectin and VE-cadherin
(Figure 3C). In addition, they also
coexpressed common hematopoietic and endothelial markers, including
C-kit (Figure 3A), PECAM, and CD13.
CD34+VEGFR-2+ cells also expressed CXCR-4, the
chemokine receptor for SDF-1 (Figure 3B). Among all of these markers,
AC133 was the only specific marker that was expressed on
CD34+ VEGFR-2+ cells but was absent on both
resting and activated mature HUVECs. VEGFR-2+ cells did not
express myelomonocytic markers, including CD15 and CD14.



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| Fig 3.
Phenotypic characterization of circulating endothelial
cells and CEPs.
Circulating VEGFR-2 endothelial cells express common
hematopoietic and endothelial markers, such as C-kit (A), CD13, and
PECAM as well as endothelial-specific markers, including E-selectin and
VE-cadherin (C). The chemokine receptor for SDF-1, CXCR-4, is expressed
on almost all of the CD34+VEGFR-2+ cells (B).
VEGFR-2+ cells do not express myelomonocytic specific
markers, including CD15 and CD14.
|
|
SDF-1 and VEGF induce migration of
CD34+VEGFR-2+
cells.
Although mature endothelial cells grow in an anchorage-dependent
manner, their capacity to respond to chemotactic factors can be
assessed using a Boyden chamber transmigration assay. In these studies,
adherent populations of mature endothelial cells are removed by
collagenase digestion, and their capacity for migration is examined in
collagen-coated Boyden chambers.
A distinctive feature of freshly isolated
CD34+VEGFR-2+ cells was their lack of capacity
to adhere to extracellular matrix at the time of isolation. Therefore,
their capacity to respond to chemotactic factors could readily be
examined by a simple transmigration assay designed for nonadherent
cells. Among the known chemotactic factors, SDF-1 has been shown to
induce migration of CD34+ hematopoietic stem cells. Given
that CD34+VEGFR-2+ cells express CXCR-4, we
explored the possibility that SDF-1 may also induce migration of
nonadherent putative CEPs. In response to SDF-1, 45% ± 2.5% of
CD34+VEGFR-2+ migrated to the lower chamber
within 3 hours. In addition, an important aspect of angiogenic
properties of VEGF is its capacity to induce endothelial cell
migration.20,21 VEGF induced migration of 41% ± 3%
of CD34+VEGFR-2+ cells added to the upper
chamber, compared to 7.1 ± 1.2% migrated cells in control group
(Figure 4).

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| Fig 4.
Migration and differentiation of CEPs.
(A) Freshly isolated CD34+ cells at 105 per
well containing 2 × 103
CD34+VEGFR-2+ cells were placed in the
upper chamber of 5-µ Costar transwell plates. Immediately, SDF-1 (200 ng/mL) or VEGF (100 ng/mL) was added in the lower chamber and, after 3 hours, migrated cells were quantified for the presence of CD34+
VEGFR-2+ endothelial colonies. As a control, serum
and cytokine-free media were used in the lower chamber in a separate
experiment. (B) Incubation of migrated
CD34+ cells with VEGF and FGF-2 on collagen-coated plastic
dishes for 2 weeks resulted in differentiation of
CD34+VEGFR-2+ cells into adherent endothelial
cell monolayers. Adherent endothelial colonies expressed
endothelial-specific markers E-selectin, VE-cadherin, and vWF but did
not express AC133 (magnification 200x). E-selectin expression was
induced by IL-1 stimulation.
|
|
Incubation of freshly isolated, nonadherent
CD34+VEGFR-2+ in medium containing VEGF and
FGF-2 in collagen-coated plastic dishes for 2 weeks resulted in
differentiation of CD34+VEGFR-2+ cells into
adherent monolayers of endothelial cells. The newly formed endothelial
colonies, which were vWF+ (Figure
4A,
B) and VE-cadherin+, did not express AC133, thus supporting
the notion that circulating AC133+VEGFR-2+
cells may be considered endothelial cells with CEP potential.

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| Fig 5.
Plating efficiency of CD34+ cells to form
endothelial cell colonies.
A highly pure population of CD34+ cells was isolated from
human FL cells and maintained in VEGF (10 ng/mL) and FGF-2 (2 ng/mL).
VEGFR-2+ cells were isolated using Biotin-labeled
anti-VEGFR-2 MoAb and Streptavidin Dynal magnetic beads. Isolated cells
were incubated in EC-specific media (containing FGF-2+ and
VEGF) in limiting dilutions approximating 1 single cell per well, and
after 10-14 days endothelial colonies were quantified using Dil-Ac-LDL
labeling. Typical Dil-Ac-LDL± endothelial cells (A)
within an adherent endothelial colony (A,B; phase contrast microscopy
350 × ) are shown. Maintaining of the endothelial colonies in
the FGF-2 and VEGF resulted in the proliferation of characteristic
endothelial cobblestone colonies (D), where most of cells were
Dil-Ac-LDL+ (C,D; 200 × ).
|
|

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| Fig 6.
Colonization of LVADs with
AC133+VEGFR-2+ cells.
An LVAD opened after explantation (A) 28 days after placement revealed
formation of neo-intima on both the sintered titanium housing (right)
and the polyurethane diaphragm (left) surfaces. The
phenotype of the mononuclear cells derived from the neo-intima formed,
analyzed by dual-color flow cytometry, demonstrated the presence of
AC133+VEGFR+ (B) as well as
CD34+VEGFR-2+ (C) endothelial precursor cells.
|
|
To quantitate the plating efficiency of VEGFR-2+ cells to
form adherent endothelial cell colonies, freshly isolated
CD34+ cells from human FL were maintained in VEGF and FGF-2
for 48 hours to remove the adherent mature cells. Subsequently,
nonadherent VEGFR-2+ cells were isolated by magnetic beads
and plated in limiting dilutions approximating 1 single cell per well.
After 10 to 14 days, adherent endothelial cell colonies were identified
by Dil-Ac-LDL labeling (Figure 5). The number of endothelial cell
colonies varies with the extent of dilution, being the highest in 1:2
dilution, where 24 colonies were detected. On average, of the 500 VEGFR+ cells plated, 15 Dil-Ac-LDL+ colonies
could be detected, giving rise to a plating efficiency of 3%. Given
that higher dilution resulted in higher numbers of EC colonies, this
suggests that accessory cells may facilitate differentiation of
VEGFR-2+ cells to endothelial colonies.
LVAD neo-intimal surfaces are colonized with
AC133+VEGFR-2+
cells.
We have previously shown that surfaces of LVADs in contact with
circulating blood are colonized with CD34+ cells with high
proliferative capacity, giving rise to a biologically nonthrombogenic
neo-intima. Close scrutiny of the LVAD surfaces shows that
4 ± 1% of the mononuclear cells express AC133+ and
VEGFR-2+ cells, suggesting that circulating CEPs have the
capacity to colonize neo-intimal surfaces (Figure 6). The presence of
AC133+VEGFR-2+ cells detected on LVADs was more
prominent in formed neo-intima explanted early after operation (28 days).
 |
Discussion |
Isolation, identification, and characterization of CEP cells have
been hampered by the absence of (1) specific endothelial markers to
differentiate between CEPs and contaminating sloughed endothelial cells
and hematopoietic progenitor/stem cells and (2) functional assays to
differentiate between mature endothelial cells and CEPs. In this
report, we have found that AC133, an early hematopoietic stem cell
marker, is expressed on a large subset of CEPs but not on the mature
endothelium. The percentage of CD34+ cells expressing
AC133+ and VEFGR2+ cells is only 2% of
circulating CD34+ cells. This figure is much less than the
percentage of CD34+ VEGFR-2+ cells previously
reported by other groups.17 Using a polyclonal antibody to
the intracellular domain of VEGFR-2, another group showed that 27% of
CD34+ cells were also VEGFR-2+. However, we
have used a specific MoAb to the extracellular domain of VEGFR-2,
allowing a more accurate estimation of the circulating CD34+VEGFR-2+ cells. In addition, because AC133
is expressed on putative CEPs, the remaining circulating
AC133 but CD34+VEGFR-2+
cells may represent a more mature differentiated population of endothelial cells.
We have also demonstrated that CD34+ cells coexpressing
AC133 and CD34 are functionally nonadherent endothelial cells that have
the capacity to migrate and differentiate into mature adherent endothelial cells. VEGF and FGF-2 are 2 growth factors that have been
shown to promote the growth of angioblasts. Incubation of CD34+-derived VEGFR-2+ cells with VEGF and
FGF-2 in the presence of collagen results in differentiation of
nonadherent AC133+VEGFR-2+ into mature
AC133 VEGFR-2+ cells.
Adherent, mature endothelial cells grow in a typical cobblestone manner
and express endothelial cell markers, including VE-cadherin; they also
up-regulate E-selectin upon activation with IL-1 . Formation of
mature endothelium from CEPs requires at least a 2-week period, in
contrast to the growth pattern of circulating mature endothelial cells,
which attach and proliferate immediately after placement in culture medium.
Many studies have shown that endothelial cells can be detected in the
peripheral circulation as a result of trauma or pathologic states.
However, these studies have not provided data as to what percent of the
circulating endothelial cells reported are indeed unique endothelial
precursor cells that may contribute to postnatal angiogenesis. Based on
our results, cytokine-induced mobilization of CD34+ cells
results in the circulation of VEGFR-2+ cells, which have
the capacity to migrate and differentiate into adherent endothelial
colonies. The percentage of CEPs may be modulated by pathophysiologic
processes, such as tumor neoangiogenesis and wound healing. On the
other hand, vascular injury due to trauma or increased shear stress may
induce nonspecific detachment of mature endothelial cells into circulation.
Vascular implants such as LVADs provide a useful model to study the
contribution of CEPs to neo-intima formation. The textured surfaces of
these devices are colonized by a nonthrombogenic cellular neo-intima
that is formed within the first few weeks of implantation. Detection
of CD34+VEGFR-2+ and
AC133+VEGFR-2+ cells in the LVAD neo-intima
demonstrates that successful angiogenesis in vivo may be achieved by
mobilization and recruitment of CEP to the sites of vascular injury
such as LVAD surfaces.
Selective homing and recruitment of CEPs into the tumor vascular bed or
sites of vascular injury may be mediated through interaction with
specific chemokines and adhesion molecules. CXCR-4, the natural receptor for the chemokine SDF-1, is expressed on endothelial cells.23,24 However, although SDF-1 induces calcium fluxes in mature endothelial cells, its exact function in the regulation of
angiogenesis remains unknown. CXCR-4 knock-out mice are not viable and
have multiple defects, including angiogenesis, suggesting that this
receptor may play a role in vascular remodeling and, possibly,
trafficking of CEPs.25,26 We demonstrate that almost all
nonadherent CD34+VEGFR-2+ cells express
functional CXCR-4. SDF-1 induced migration of
CD34+VEGFR-2+ cells that, in the presence of
VEGF, FGF-2, and collagen, differentiate into adherent endothelial
monolayers. These data suggest that SDF-1 released by tumor cells or
injured tissue may play a key role in chemoattraction of CEPs.
Migration of CEPs in response to VEGF underscores the physiologic role
of this factor in supporting various aspects of angiogenesis and also
suggest a mechanism for attracting circulating CEPs to the sites of
vascular injury or tumor vascular beds.
During embryonic development, angioblasts and primitive hematopoietic
stem cells originate from a common stem cell or
hemangioblast.27,28 Several studies have shown that
hemangioblasts express common endothelial markers, including
VEGFR-2.29 Therefore, it is possible that subsets of
CD34+VEGFR-2+ cells may have hemangioblast
potential and, under appropriate cytokine stimulation, may also have
the capacity to differentiate into hematopoietic stem cells.
In summary, our data provide evidence for a distinct population of
circulating human CD34+ cells that coexpress AC133 and
VEGFR-2 and that have the capacity to migrate and differentiate into
adherent mature endothelial cells, supporting the existence of CEPs
with the potential to contribute to postnatal angiogenesis.
Quantification of these cells in the peripheral circulation may provide
useful information regarding the contribution of CEPs in different
disease states. Our ability to isolate pure populations of these cells
will facilitate further characterization and examination of their
potential to contribute to neo-angiogenesis in wound healing and tumor growth.
 |
Footnotes |
Submitted May 14, 1999; accepted October 1, 1999.
S.R. supported by the American Heart Association Grant-In-Aid; NHLBI
grants R01-HL-58707 and R01-HL-61849; the Dorothy Rodbell Foundation
for Sarcoma Research; and the Rich Foundation. M.P. supported by a
grant from the National Childhood Cancer Foundation. M.A.S.M. supported
by NHLBI grant R01-HL-61401 and the GAR Reichman Fund of the Cancer
Center support grant CA-08748.
Reprints: Shahin Rafii, Weill Medical College of Cornell
University, Hematology-Oncology Division, 1300 York Ave, Room C-606,
New York, NY 10021; e-mail:srafii{at}mail.med.cornell.edu.
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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K. Ieta, F. Tanaka, N. Haraguchi, Y. Kita, H. Sakashita, K. Mimori, T. Matsumoto, H. Inoue, H. Kuwano, and M. Mori
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P. Atluri, C. M. Panlilio, G. P. Liao, E. E. Suarez, R. C. McCormick, W. Hiesinger, J. E. Cohen, M. J. Smith, A. B. Patel, W. Feng, et al.
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A. Whittaker, J. S. Moore, M. Vasa-Nicotera, S. Stevens, and N. J. Samani
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M. L. Balestrieri, C. Schiano, F. Felice, A. Casamassimi, A. Balestrieri, L. Milone, L. Servillo, and C. Napoli
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D. Tang, J. Lu, J. P. Walterscheid, H.-H. Chen, D. A. Engler, T. Sawamura, P.-Y. Chang, H. J. Safi, C.-Y. Yang, and C.-H. Chen
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M. Mints, M. Jansson, B. Sadeghi, M. Westgren, M. Uzunel, M. Hassan, and J. Palmblad
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W Wojakowski, M Kucia, M Kazmierski, M Z Ratajczak, and M Tendera
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Heart,
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M. E. Kleinman, M. R. Greives, S. S. Churgin, K. M. Blechman, E. I. Chang, D. J. Ceradini, O. M. Tepper, and G. C. Gurtner
Hypoxia-Induced Mediators of Stem/Progenitor Cell Trafficking Are Increased in Children With Hemangioma
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M. Diez, J. A. Barbera, E. Ferrer, R. Fernandez-Lloris, S. Pizarro, J. Roca, and V. I. Peinado
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Cardiovasc Res,
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T. Kanayasu-Toyoda, A. Ishii-Watabe, T. Suzuki, T. Oshizawa, and T. Yamaguchi
A New Role of Thrombopoietin Enhancing ex Vivo Expansion of Endothelial Precursor Cells Derived from AC133-positive Cells
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D. Santini, B. Vincenzi, and G. Tonini
Zoledronic Acid and Angiogenesis
Clin. Cancer Res.,
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S. Farha, K. Asosingh, D. Laskowski, L. Licina, H. Sekigushi, D. W. Losordo, R. A. Dweik, H. P. Wiedemann, and S. C. Erzurum
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Z. Zhou, K. Reddy, H. Guan, and E. S. Kleinerman
VEGF165, but not VEGF189, Stimulates Vasculogenesis and Bone Marrow Cell Migration into Ewing's Sarcoma Tumors In vivo
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X. Wu, M. W. Lensch, J. Wylie-Sears, G. Q. Daley, and J. Bischoff
Hemogenic Endothelial Progenitor Cells Isolated from Human Umbilical Cord Blood
Stem Cells,
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H. Shmilovich, V. Deutsch, A. Roth, H. Miller, G. Keren, and J. George
Circulating endothelial progenitor cells in patients with cardiac syndrome X
Heart,
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Y. Wang, Y. Zheng, W. Zhang, H. Yu, K. Lou, Y. Zhang, Q. Qin, B. Zhao, Y. Yang, and R. Hui
Polymorphisms of KDR Gene Are Associated With Coronary Heart Disease
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M. Ferrario, M. Massa, V. Rosti, R. Campanelli, M. Ferlini, B. Marinoni, G. M. De Ferrari, V. Meli, M. De Amici, A. Repetto, et al.
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W. Wojakowski, M. Kazmierski, B. Korzeniowska, and M. Tendera
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Eur. Heart J.,
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J. Y. Liu, D. D. Swartz, H. F. Peng, S. F. Gugino, J. A. Russell, and S. T. Andreadis
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Cardiovasc Res,
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A. Schmidt, K. Brixius, and W. Bloch
Endothelial Precursor Cell Migration During Vasculogenesis
Circ. Res.,
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F. Timmermans, F. Van Hauwermeiren, M. De Smedt, R. Raedt, F. Plasschaert, M. L. De Buyzere, T. C. Gillebert, J. Plum, and B. Vandekerckhove
Endothelial Outgrowth Cells Are Not Derived From CD133+ Cells or CD45+ Hematopoietic Precursors
Arterioscler. Thromb. Vasc. Biol.,
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D. Yu, X. Sun, Y. Qiu, J. Zhou, Y. Wu, L. Zhuang, J. Chen, and Y. Ding
Identification and Clinical Significance of Mobilized Endothelial Progenitor Cells in Tumor Vasculogenesis of Hepatocellular Carcinoma
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E. Rohde, C. Bartmann, K. Schallmoser, A. Reinisch, G. Lanzer, W. Linkesch, C. Guelly, and D. Strunk
Immune Cells Mimic the Morphology of Endothelial Progenitor Colonies In Vitro
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M. Nagano, T. Yamashita, H. Hamada, K. Ohneda, K.-i. Kimura, T. Nakagawa, M. Shibuya, H. Yoshikawa, and O. Ohneda
Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood
Blood,
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C. K. Kissel, R. Lehmann, B. Assmus, A. Aicher, J. Honold, U. Fischer-Rasokat, C. Heeschen, I. Spyridopoulos, S. Dimmeler, and A. M. Zeiher
Selective Functional Exhaustion of Hematopoietic Progenitor Cells in the Bone Marrow of Patients With Postinfarction Heart Failure
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C. V. Pfenninger, T. Roschupkina, F. Hertwig, D. Kottwitz, E. Englund, J. Bengzon, S. E. Jacobsen, and U. A. Nuber
CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells
Cancer Res.,
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D. J. Nolan, A. Ciarrocchi, A. S. Mellick, J. S. Jaggi, K. Bambino, S. Gupta, E. Heikamp, M. R. McDevitt, D. A. Scheinberg, R. Benezra, et al.
Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization
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L. Bezuidenhout, M. Bracher, G. Davison, P. Zilla, and N. Davies
Ang-2 and PDGF-BB cooperatively stimulate human peripheral blood monocyte fibrinolysis
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G. Invernici, C. Emanueli, P. Madeddu, S. Cristini, S. Gadau, A. Benetti, E. Ciusani, G. Stassi, M. Siragusa, R. Nicosia, et al.
Human Fetal Aorta Contains Vascular Progenitor Cells Capable of Inducing Vasculogenesis, Angiogenesis, and Myogenesis in Vitro and in a Murine Model of Peripheral Ischemia
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J. M. Melero-Martin, Z. A. Khan, A. Picard, X. Wu, S. Paruchuri, and J. Bischoff
In vivo vasculogenic potential of human blood-derived endothelial progenitor cells
Blood,
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P. Dentelli, A. Rosso, A. Balsamo, S. Colmenares Benedetto, A. Zeoli, M. Pegoraro, G. Camussi, L. Pegoraro, and M. F. Brizzi
C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium
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A. V. R. Santhanam, L. A. Smith, T. He, K. A. Nath, and Z. S. Katusic
Endothelial Progenitor Cells Stimulate Cerebrovascular Production of Prostacyclin By Paracrine Activation of Cyclooxygenase-2
Circ. Res.,
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H. D. Theiss, R. David, M. G. Engelmann, A. Barth, K. Schotten, M. Naebauer, B. Reichart, G. Steinbeck, and W.-M. Franz
Circulation of CD34+ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM)
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S. Schwartzenberg, V. Deutsch, S. Maysel-Auslender, S. Kissil, G. Keren, and J. George
Circulating Apoptotic Progenitor Cells: A Novel Biomarker in Patients With Acute Coronary Syndromes
Arterioscler. Thromb. Vasc. Biol.,
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A. Norden-Zfoni, J. Desai, J. Manola, P. Beaudry, J. Force, R. Maki, J. Folkman, C. Bello, C. Baum, S. E. DePrimo, et al.
Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor
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V. Balasubramaniam, C. F. Mervis, A. M. Maxey, N. E. Markham, and S. H. Abman
Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia
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Y. Yamada, S.-i. Yokoyama, X.-D. Wang, N. Fukuda, and N. Takakura
Cardiac Stem Cells in Brown Adipose Tissue Express CD133 and Induce Bone Marrow Nonhematopoietic Cells to Differentiate into Cardiomyocytes
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V. L.T. Ballard and J. M. Edelberg
Stem Cells and the Regeneration of the Aging Cardiovascular System
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S. Caballero, N. Sengupta, A. Afzal, K.-H. Chang, S. Li Calzi, D. L. Guberski, T. S. Kern, and M. B. Grant
Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells
Diabetes,
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C. Igreja, M. Courinha, A. S. Cachaco, T. Pereira, J. Cabecadas, M. G. da Silva, and S. Dias
Characterization and clinical relevance of circulating and biopsy-derived endothelial progenitor cells in lymphoma patients
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C. Murphy, G. S. Kanaganayagam, B. Jiang, P. J. Chowienczyk, R. Zbinden, M. Saha, S. Rahman, A. M. Shah, M. S. Marber, and M. T. Kearney
Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men
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A. Casamassimi, M. L. Balestrieri, C. Fiorito, C. Schiano, C. Maione, R. Rossiello, V. Grimaldi, V. Del Giudice, C. Balestrieri, B. Farzati, et al.
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P. Madeddu and C. Emanueli
Switching on Reparative Angiogenesis: Essential Role of the Vascular Erythropoietin Receptor
Circ. Res.,
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M. Hristov, A. Zernecke, K. Bidzhekov, E. A. Liehn, E. Shagdarsuren, A. Ludwig, and C. Weber
Importance of CXC Chemokine Receptor 2 in the Homing of Human Peripheral Blood Endothelial Progenitor Cells to Sites of Arterial Injury
Circ. Res.,
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G. L. Hoetzer, G. P. Van Guilder, H. M. Irmiger, R. S. Keith, B. L. Stauffer, and C. A. DeSouza
Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men
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M. C. Yoder, L. E. Mead, D. Prater, T. R. Krier, K. N. Mroueh, F. Li, R. Krasich, C. J. Temm, J. T. Prchal, and D. A. Ingram
Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals
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T. Chen, H. Bai, Y. Shao, M. Arzigian, V. Janzen, E. Attar, Y. Xie, D. T. Scadden, and Z. Z. Wang
Stromal Cell-Derived Factor-1/CXCR4 Signaling Modifies the Capillary-Like Organization of Human Embryonic Stem Cell-Derived Endothelium In Vitro
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A. O Robb, N. L Mills, D. E Newby, and F. C Denison
Endothelial progenitor cells in pregnancy
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