Placenta 34, Supplement A, Trophoblast Research, Vol.

27 (2013) S62eS67

Contents lists available at SciVerse ScienceDirect

Placenta
journal homepage: www.elsevier.com/locate/placenta

Review: Endothelial progenitor cells in pregnancy and obstetric

pathologies
I.P. Crocker a, b, *, P.I. Sipos a, b
a
Maternal and Fetal Health Research Centre, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK
b
Maternal and Fetal Health Research Centre, St. Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic
Health Science Centre, Manchester M13 9WL, UK

a r t i c l e i n f o a b s t r a c t

Article history: Since their discovery, endothelial progenitor cells (EPCs) have generated considerable interest in vascular
Accepted 3 January 2013 biology. They are a heterogeneous population of cells that exist in both the fetus and adult, and are
mobilized to support de novo vessel formation or encourage vascular health. This review summarizes our
Keywords: understanding of these cells in pregnancy, paying particular attention to their physiological role in
Endothelial progenitor cells placental development and the uterus, alongside their involvement in related obstetric pathologies.
Placenta
Ó 2013 Published by IFPA and Elsevier Ltd.
Uterus
Pre-eclampsia
Intrauterine growth restriction

1. Introduction
Vasculogenesis and angiogenesis are processes of new blood
vessel generation. Before 1997, vasculogenesis, de novo vessel for-
mation through differentiation of angioblasts, was believed to be
restricted to embryonic development, with angiogenesis, forma-
tion from pre-existing vessels, superseding postnatally. In 1997
Asahara et al. [1] published the first report of circulating bone-
marrow derived cells in humans capable of differentiation into
mature endothelia and participation in neovascularisation. Shi
et al., then showed comparable cells endothelialising intra-aortic
Dracon grafts in dogs [2]. These two studies established the exis-
tence of endothelial progenitor cells (EPCs) in the adult, with
functional similarities to embryonic angioblasts. With this discov-
ery came a paradigm shift in vascular biology, with the recognition
that neovascularisation in adults could depend, at least in part, on
putative postnatal vasculogenesis. Subsequent studies confirmed
that EPCs are mobilized from the bone-marrow (and possibly from
other organs) and home to sites of tissue ischemia or endothelial
damage, adopting a more mature endothelial phenotype and con-
tributing to de novo vessel formation. Thus, EPCs play an integral
role in endothelium regeneration, vessel repair and maintenance.
* Corresponding author. Maternal and Fetal Health Research Centre, Institute of
Human Development, Faculty of Medical and Human Sciences, University of
Manchester, Reception, 5th Floor (Research), St Mary’s Hospital, Oxford Road,
Manchester, M13 9WL, UK. Tel.: þ44 (0) 161 701 6973.
E-mail address: Ian.Crocker@manchester.ac.uk (I.P. Crocker).
Since 1997, the number of investigations into human EPCs has
grown exponentially. The bulk of this research has focused on adult
cardiovascular disease, with scant attention to the fetus, placenta or
pregnancy. The fact that vessel formation and vascular expansion
are implicit to pregnancy, and that the presence and activity of these
cells is greater in the fetus compared to adults, has generally gone
unnoticed. This article reviews current evidence of EPC involvement
in human pregnancy. It appraises the current literature, introduces
some preliminary findings and discusses possibilities for further
obstetric research and intervention. The involvement of EPCs in the
pathophysiology of pre-eclampsia, intrauterine growth restriction
(IUGR) and fetal programming is considered.
2. Origins of EPCs
In recent years EPCs, and more specifically their absence, have
emerged as risk factors for cardiovascular disease, with good evi-
dence for a role in endothelial homeostasis and repair. Independent
of more classic risk factors, the levels of these cells can predict
endothelial dysfunction in healthy individuals, and cardiovascular
events in patients with coronary artery disease [3,4]. A similar
reduction in circulating EPCs is noted in a variety of other vascular-
related conditions, including diabetes [5], peripheral vascular dis-
ease, rheumatoid arthritis [6] and obesity [7], but the mechanisms
underlying these associations are uncertain.
Although not restricted to bone marrow, the majority of EPCs
reside within its microenvironment, termed the stromal or osteo-
blast niche. In this state they are tethered by integrins to the stromal

0143-4004/$ e see front matter Ó 2013 Published by IFPA and Elsevier Ltd.
http://dx.doi.org/10.1016/j.placenta.2013.01.003
 I.P. Crocker, P.I. Sipos / Placenta 34, Supplement A, Trophoblast Research, Vol. 27 (2013) S62eS67
cells until they are transferred to the vascular niche for subsequent
egress to the peripheral circulation. All classes of EPCs are derived
from hemangioblasts, embryonic or adult, which differentiate to
endothelial cells or myeloid progenitors (Fig. 1). Ultimately, whether
all endothelial cell progenitors proceed through a “monocytic” phase
is unclear. However, at least two fundamentally different types of
EPCs may be mobilized, CD45 and CD34 expressing hematopoietic-
like cells and CD34 positive CD45 negative “endothelial-like”
equivalents [8]. These cells play a critical and some say comple-
mentary role in blood vessel formation and repair [9].
The proliferation and mobilization of EPCs from the bone-marrow
involve a complex interplay of adhesion molecules, chemokines,
cytokines and proteinases. In vascular injury and tissue ischemia,
vascular endothelial growth factor (VEGF) and stromal cell-derived
factor-1 (SDF-1) are thought to be particularly important, upregu-
lated in the circulation by hypoxia-inducible factor 1 (HIF-1) [10].
Nitric oxide (NO) is also a key intermediary, as the activation of
endothelial nitric oxide synthase (eNOS) in the bone marrow is
considered a common mobilizing reaction of EPCs to VEGF, estrogen,
insulin-like growth factor I (IGF-I) and erythropoietin [11]. In lib-
erating EPCs, SDF-1 and NO activate matrix metalloproteinase 9
(MMP-9), which in turn catalyzes the proteolysis of Kit Ligand (KitL),
severing its adhesion to c-kit receptor and freeing the cells from their
bone marrow niche. In mice, acute administration of this receptor, in
its soluble form, sc-kit, increases mobilization of EPCs, theoretically
disrupting these c-kit - KitL interactions [12].
3. Characterization of EPCs
The characterization of EPCs is highly contentious. In cell cultures
of unfractionated mononuclear cells, at least two fundamentally
different types of EPCs have been generated, early- and late-
outgrowth cells, respectively. The early outgrowth cells are referred
to as colony-forming unit endothelial cells (CFU-ECs) or circulating
angiogenic cells (CACs), whilst alternative conditions yield endo-
thelial colony forming cells (ECFCs) (Fig. 1). These cells appear late in
Fig. 1. Pathways to EPC ontogeny. Primitive haemangioblasts in the bone marrow give rise to myeloid and endothelial progenitors which yield early outgrowth, ‘endothelial-like’
colony-forming unit cells (ECFCs) or spindle-shaped circulating angiogenic cells (CACs). The relative expression of cell surface markers identifies these differentiation pathways.
ECFCs eventually form mature endothelium, whilst CACs orchestrate neovascularisation.
S63
culture, are highly proliferative, can be clonally expanded, but are
otherwise indistinguishable from mature endothelial cells. CACS and
ECFCs may work synergistically in vivo, CACs primarily enhancing the
survival and function of ECFCs by providing copious angiogenic fac-
tors (NO, VEGF, IGF-I etc), and ECFCs participating in blood vessel and
endothelium formation per se [9]. Flow cytometry is also used to
enumerate these groups. These approaches most often use CD34 or
CD133 in combination with VEGFR-2 (KDR), but again a consensus is
far from reached. In general, ECFCs are often characterized as CD31þ/
CD34þ/CD45/VEGFR-2þ/CD133, CACs as CD31þ/CD34þ/CD45þ/
dim
/CD14þ/CD133þ/ [13]. These techniques are improved by
excluding false positive events, such as dead cells and CD3þ T cells.
4. EPCs and the uterus
Extensive remodeling and growth within the human endome-
trium precedes implantation. Physiological angiogenesis is funda-
mental to the proliferative and secretory phases of the menstrual
cycle. The involvement of adult stem cells in the cyclic regeneration
and shedding of the endometrium was first suggested by Chan et al.,
in 2004, following the clonogenic derivation of human endometrial
epithelial and stromal cells [14]. Although, EPCs had already been
defined in the endometrium in the mouse at this time, their role had
not been confirmed [15]. In 2007, bone-marrow derived EPCs were
shown to contribute to de novo blood vessel formation in the mouse
endometrium [16]. In verifying EPC participation in the menstrual
cycle, flow cytometric determinations of circulating human cells
were performed. Although not definitive, these studies showed el-
evations in the secretory and follicular phases, implying steroid
regulation and endometrial regenerative contributions [17,18].
Given that local factors such as estradiol, tumor necrosis factor-
a (TNF-a), interleukin (IL)-6, VEGF and intercellular adhesion mol-
ecule (ICAM)-1, participate in EPC migration and trafficking, their
contribution to the human cycle was anticipated, but sex steroids
and circulating inflammatory mediators have yet to be correlated
with peripheral EPCs in the non-pregnant state [17].
S64 I.P. Crocker, P.I. Sipos / Placenta 34, Supplement A, Trophoblast Research, Vol. 27 (2013) S62eS67
Throughout pregnancy, the uterus undergoes widespread vas-
culature adaptations. In addition to extensive vasodilatation and
anastomosis [19], uterine spiral arteries undergo elaborate
remodeling, mediated by interstitial and endovascular trophoblast.
During trophoblast invasion, maternal spiral arteries are trans-
formed into wide-bore conduits, in which the endothelia are first
damaged and then replenished. Although trans-differentiation of
trophoblast was initially conceived to replace these losses, current
evidence supports re-endothelialisation [20]. In preliminary stud-
ies, we have investigated the involvement of fetal EPCs in these
uterine adaptive events [21]. This concept was derived in the
knowledge that adult EPC efficiency is dramatically surpassed by
their fetal counterparts [22]. In mouse models, we tentatively
concluded that fetal ECFCs transmigrate into the maternal blood-
stream and home to locations of maternal vasculogenesis, primarily
microvessels of the pregnant uterus [21]. If verified, this chimerism
offers the tantalizing involvement of fetal EPCs in human uterine
adaptations, and provides potential alternative participants in
spiral artery endothelium restoration.
5. EPCs and endometriosis
In addition to the recruitment of EPCs into the human endo-
metrium, either in pregnancy or the menstrual cycle, the possibility
that these cells are liberated in retrograde fashion is also enter-
tained. As circulating endothelial cells are shed artificially or
spontaneously from vessels, particularly during trauma, it is con-
ceivable that endometrial EPCs slough off from endometrial vessels
and are mobilized to ectopic sites through blood or lymphatic
systems. In a unifying concept for the pathogenesis of endome-
triosis, Maruyama and colleagues proposed that these endometrial
EPCs migrate into the parenchyma of ectopic organs and differ-
entiate into endometrial cell components, thus giving rise to
endometrial lesions [23]. In support, circulating EPCs are upregu-
lated in a mouse model of endometriosis [24], whilst the same
group recently showed that endometrial stem/progenitor pop-
ulations display significant endothelial-like characteristics, along-
side more traditional endometrial progenitor properties [25].
6. EPCS in the fetus and placenta
Although EPCs are recruited from the bone marrow, Ingram
et al. used single cell clonogenic assays to show that a small per-
centage of human umbilical vein endothelial cells (HUVEC) and
human aortic endothelial cells contain endothelial colony-forming
cells of low proliferative potential (LPP-ECFCs), generating colonies
with less than 500 cells, and high proliferative potential (HPP-
ECFCs), with improved telomerase activity [22]. In head-to-head
comparisons, it was clear not only that these fetal EPCs were
more abundant and active than their adult counterparts, but that
this high proliferative phenotype was absent in adults altogether
[22]. As several organs, including the placenta, are capable of pro-
ducing hematopoietic cells [26], it is possible that the placenta is
a primary or supplementary source of EPCs for the fetus. Given the
unique anatomical position and accessibility of the human pla-
centa, this idea is readily tested. In further preliminary studies [27],
we used stringent and accepted markers of ECFCs and CACs in
uncomplicated pregnancies, and showed higher levels of both cells
in the umbilical arteries than vein, drawing the likely conclusions
that: (i) the human placenta is a doubtful source of EPCs for the
fetus, and (ii) that the placenta retains EPCs on passage through the
organ [27]. Although these observations await confirmation, we
tentatively propose that EPCs have a likely vascular role in the
placenta, even in late gestation when angiogenesis is curtailed.
7. EPCs and placental pathologies
Within the human placenta, angiogenic activities are orchestrated
by numerous factors, including oxygen tension and pro-and anti-
angiogenic mediators, such as placental growth factor (PlGF), VEGF
and its neutralizing soluble receptor sVEGFR-1. With studies in pre-
eclampsia indicating variations of such molecules at the placental
level [28], their impact on fetal endothelial cells has also been con-
sidered. In vitro, and thus in the absence of these factors, isolated
HUVECs, i.e. mature endothelial cells, from preeclamptic pregnancies
have shown inherent alterations in cell permeability, morphology,
mechanical properties, release of vasodilatory mediators and
enhanced angiogenic capacity [29e32]. Although their significance is
unproven, these anomalies are attributed to intrinsic differences or
environmental adaptations prior to cell isolation, i.e. the angiogenic
feto-placental milieu. In similar experiments, cord-derived EPCs from
women with severe pre-eclampsia have shown a reduction in num-
bers and attenuated proliferation, migration and vasculogenic ca-
pacity [33,34]. These anomalies are specifically related to diminished
cord plasma free VEGF and overabundance of sVEGFR-1 (sFlt-1) [35].
In line with pre-eclampsia studies, attenuated changes in cord
blood VEGF and sFlt-1 have also been recorded in cases of IUGR, i.e.
pregnancies more associated with abnormal placental angiogenesis
and feto-placental vascular anomalies [36]. Our initial studies of
cord blood in IUGR have considered EPC availability and in vitro
activities [37]. In comparison with uncomplicated pregnancies,
provisional flow cytometry data, suggested that fewer EPCs (CACs
and ECFCs) were present in growth restricted pregnancies and that
placental sequestration was also impaired [37]. The culture prop-
agation of ECFCs confirmed these findings, with fewer colonies and
longer doubling times, hinting at diminished proliferative capacity
[37]. In support, Hwang et al. recently confirmed these prolonged
differentiation times and highlighted impaired senescence through
diminished telomerase and increased b-galactosidase activity [38].
Moreover, in a related study, Ligi et al. investigated whether low
birthweight and prematurity could impact the angiogenic prop-
erties of cord blood ECFCs [39]. As well as deficits in number, and
angiogenic defects in vitro and in vivo, these investigators under-
took gene profiling and highlighted increased expression of anti-
angiogenic genes, predominately thrombospondin 1, as a possible
explanatory factor. From these studies, it remains uncertain
whether prior disturbance in ECFC function results in defective
placental angiogenesis/vasculogenesis, thus leading to IUGR, or
whether inadequate placentation might occur for other reasons,
but with equal and lasting effects on ECFC numbers and function.
Regardless, these studies offer new perspectives on placental pa-
thologies, and interesting novel pathways to fetal deprogramming.
8. Circulating EPCs in pregnancy
Human pregnancy requires sustained cardiovascular adapta-
tions, typified by a fall in peripheral resistance, offsetting elevations
in cardiac output and plasma volume. To overcome the ‘vascular
stress’ of pregnancy, the maternal endothelium shows enhanced
reactivity and an inflated dependence on autocrine/paracrine va-
sodilators, including NO and prostacyclin. In assessing EPCs, cross-
sectional studies of circulating cells in uncomplicated pregnancies
have been published, with the range of methods generally defying
direct comparisons. From flow cytometric enumerations, Luppi
et al. reported a progressive increase in circulating CD133þ/VEGFR-
2þ cells from the first trimester onwards, with a significant rise in
CD34þ/VEGFRþ cells nearer term [40]. Typically their first trimester
values were below detection, similar to those of non-pregnant
controls. In agreement, Buemi et al. reported similar progressive
elevations [41]. However, both studies are in stark contrast to
 I.P. Crocker, P.I. Sipos / Placenta 34, Supplement A, Trophoblast Research, Vol. 27 (2013) S62eS67 S65

Matsubara and colleagues, who observed a significant decline in attributed to structural alterations in heparan sulfate proteoglycans
CD34þ/CD133þ/KDRþ cells with gestation and a concomitant [53], perhaps tying pregnancy complications to maternal age.
reduction in EPC numbers and restricted responses to TNF-a and Within the fetus, aberrant EPC numbers and function could the-
angiotensin II in culture [42]. oretically impact the embryonic endothelium directly and impair the
Culture generated EPCs are generally considered more prolif- formation of normal placental vessels, thus restricting nutrient
erative and abundant from the second half of pregnancy, with supply and exacerbating fetal growth restriction. As vascular repair is
a predominance of late outgrowth EPC-CFUs correlating with a perquisite for cardiovascular health, it would be predicted that fetal
serum estradiol [43,44]. Given their superior proliferative capacity, EPCs that underperform in the fetus could equally underperform in
a fetal origin was considered. However, two independent studies later life. Epidemiological evidence supports this notion, as babies
refute this idea, failing to detect the SRY gene in EPCs from pregnant affected by IUGR and pre-eclampsia show increased susceptibility to
women carrying solely male offspring [34,45]. As estrogen itself can cardiovascular disease in adulthood. If verified, EPCs could thus offer
mobilize EPCs from the bone marrow in vivo, and stimulate VEGF an explanation for Barker’s hypothesis; i.e. the association between
production and inhibit EPC senescence in vitro, it seems likely that sub-optimal intrauterine growth and adult-onset chronic disease.
hormonal conditioning is a primary means of optimizing EPCs in Undoubtedly further research is warranted.
pregnancy. In rat models of carotid injury, exogenous estradiol can As studies of EPCs move towards diagnostic and therapeutic
accelerate re-endothelialisation via EPC proliferation/mobilization exploitation, a better understanding of the subgroups involved,
[46]. Whilst additional mouse studies confirm the importance of and their interactions with the key vascular beds of pregnancy, will
the estrogen receptor (ER) in mitigating EPC responses to ischemia become a necessity. At this stage it could be envisaged that sig-
[47]. It would therefore seem that in addition to the known vaso- nificant clinical benefit may be derived. This benefit may take
protective affects of estrogens, through NO stimulation and ROS many forms: (i) the assessments of EPC numbers and function
suppression, further protection, in and outside of pregnancy, is could be used to develop diagnostic tools for related pregnancy
afforded by bolstering effects on EPC efficiency. complications, such as IUGR and pre-eclampsia; (ii) medical in-
terventions could be targeted to improve EPC activation in preg-
nancy (see Table 1 for current possibilities), and (iii) EPCs
9. EPCs and pre-eclampsia
themselves could be used as therapeutic tools, either as autologous
or donor therapies for the fetus, placenta or pregnant woman.
Despite advances, the causes of pre-eclampsia remain ill defined.
From a general perspective, the fledging trials of statins in pre-
Nevertheless, it is generally agreed that early onset cases have
eclampsia may inform this area, whilst a recent study by Wang
deficient placentation, typified by decreased spiral artery remod-
et al., has advocated integrin-linked kinase (ILK) as a target for
eling, whilst late onset syndrome is attributed more to maternal
clinical cell-based gene therapy for pre-eclampsia, after their EPC
vascular maladaptations. Vascular endothelial dysfunction precedes
transfections augmented the angiogenic properties of pre-
clinical diagnosis in both scenarios, as indicated by raised soluble
eclampsia-derived cells in vitro [54].
markers and reduced flow-mediated dilatation. For the most part,
predisposing maladies for pre-eclampsia, i.e. age, renal disease and
diabetes, have intrinsically lower EPCs [48e50]. Therefore similar Conflict of interest statement
studies have emerged for pre-eclampsia, but again with conflicting
results. Whilst Mastubara et al., reported no change in circulating We confirm that there are no known conflicts of interest asso-
EPCs in pre-eclampsia, as determined by flow cytometry [42], their ciated with this publication and there has been no significant
mononuclear derived outgrowth cells showed enhanced prolifera- financial support for this work that could have influenced its
tion upon TNF-a and angiotensin II stimulation. This finding con- outcome.
trasts with that of Sugawara and colleagues, who reported
a decrease in the number of circulating EPCs in pre-eclampsia as
defined by EPC-CFU count e a general correlate of cardiovascular Table 1
risk e and higher rates of senescence [51]. This latter study agrees Pharmaceuticals known to influence EPC number or function. Adapted from
Ref. [13].
with a more recent report of similarly diminished cells in women
with pre-eclampsia [34], but a definitive conclusion remains lack- Agent Effect on EPCs Mode of action
ing. Future investigations are needed to define the number and Angiotensin-II CAC senescence Angiotensin type 1 receptor
function of EPCs prospectively, prior to disease onset, and whether (AT1R)
Angiotensin-II Increases EPC numbers, C-kit-expression
identified distortions are a cause or consequence of this syndrome.
inhibitors migration
Erythropoietin Increases CAC number, NO-dependent
mobilization anti-
10. Clinical perspectives
apoptotic, NO-synthesis
Estradiol Mobilizes and encourages NO and MMP-9-dependent
Considering available evidence, it could be speculated that EPCs proliferation
are involved in the vascular wellbeing of the fetus, placenta and Nifedipine Increases CAC number, Unknown
perhaps even the expectant mother. From a maternal perspective, function, and resistance
to oxidative stress
EPCs may be required for systemic vascular adaptations to preg- Physical exercise Increases EPC number, NO-dependent, increases
nancy and uterine homeostasis. In pre-eclampsia it is possible that capacity inhibits apoptosis VEGF
deficiencies or functional impairments in EPCs, both CACs and PPAR-d agonists Stimulates CAC PI3K/Akt pathway.
ECFCs, may render a woman more susceptible to inflammatory or proliferation, mobilization.
Anti-apoptotic.
metabolic insults, thus exacerbating endothelial dysfunction. The
Prostaglandin E1 Enhances mobilization NO-dependent, Increased
fact that this dysfunction can persist beyond pregnancy, as defined and function CXCR4
epidemiologically, through an elevated risk of hypertension, coro- Statins Elevates EPCs in bone PI3K/Akt pathway
nary or cerebro-vascular disease [52], raises the idea that defective marrow and circulation.
EPCs are inherent and life-long. In this respect, an age-related Integrin-upregulation
Sildenafil Increases EPC numbers Unknown
decline in EPC numbers and efficiency has been noted, and
S66 I.P. Crocker, P.I. Sipos / Placenta 34, Supplement A, Trophoblast Research, Vol. 27 (2013) S62eS67

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