Cardiovascular Bioscience
The role of stem cells in vein graft remodelling
Q. Xu1
Cardiovascular Division, The James Black Centre, King’s College London, 125 Coldharbour Lane, London SE5 9NU, U.K.
Abstract
The vessel wall is a dynamic tissue that undergoes positive remodelling in response to altered mechanical
stress. A typical example is vein graft remodelling, because veins do not develop arteriosclerosis until a
vein segment is grafted on to arteries. In this process, it was observed that vascular endothelial and smooth
muscle cells of vein grafts die due to suddenly elevated blood pressure. This cell death is followed by
endothelial regeneration. Central to this theme is the essential role played by EPCs (endothelial progenitor
cells) in regenerating the lost endothelium. The mechanisms by which EPCs attach to the vessel wall
and differentiate into mature endothelial cells involve increased chemokine production and laminar shear
flow stimulation on the vessel wall. It seems that neo-endothelial cells derived from EPCs lack mature
cell functions and express high levels of adhesion molecules resulting in LDL (low-density lipoprotein)
penetration and mononuclear cell infiltration into the sub-endothelial space. Among infiltrated mononuclear
cells, there are smooth muscle progenitors that proliferate and differentiate into smooth muscle cells.
Meanwhile, stem cells present in the media and adventitia may also migrate into arteriosclerotic lesions
via the vasa vasorum that are abundant in the diseased vessels. However, the molecular events leading
to the homing, differentiation and maturation of stem/progenitor cells still needs elucidation. The present
review attempts to update the progress in stem cell research related to the pathogenesis of vein graft
arteriosclerosis or remodelling, focusing on the mechanisms by which stem/progenitor cells participate in
the development of lesions, and to discuss the controversial issues and the future perspectives surrounding
this research area.
Introduction
Stem cells have the capability to transform and replenish
the different tissue types that make up the body, and also
represent the fundamental building blocks of organ development. In general, stem cells can be divided into two broad
categories: adult (somatic) stem cells and embryonic stem
cells [1]. One of the most fascinating and important aspects
of stem cells is their ability to differentiate in vitro, via ‘progenitor cells’, into terminally differentiated somatic cells of
all tissue types, including cardiomyocytes, SMCs (smooth
muscle cells) [2,3] and endothelial cells [4]. Because of the
discovery that stem cells have a role in vascular regeneration, through differentiation into endothelial cells and SMCs,
stem cell research could be important not only for understanding the pathogenesis of arteriosclerosis, but also for the
advancement of cell-based therapies and tissue engineering.
Autologous vein grafts remain the only surgical alternative
for many types of vascular reconstruction, although
the patency rate is limited due to obliterative stenosis of the
grafted vessels. We demonstrated that the earliest cellular
event in mouse vein grafts is cell death, i.e. apoptosis and
Key words: atherosclerosis, endothelium, progenitor cell, smooth muscle cell, stem cell, vein
graft remodelling.
Abbreviations used: EPC, endothelial progenitor cell; GFP, green fluorescent protein; β-gal,
β-galactosidase; HDAC, histone acetyltransferase; LDL, low-density lipoprotein; NOS, nitric oxide
synthase; eNOS, endothelial NOS; iNOS, inducible NOS; PDGF, platelet-derived growth factor;
SDF, stromal cell-derived factor; SMC, smooth muscle cell; VEGF, vascular endothelial growth
factor; VEGFR, VEGF receptor; X-gal, 5-bromo-4-chloroindol-3-yl β-d-galactopyranoside.
1
email [email protected]
necrosis [5]. Others have shown extensive loss of endothelial
cells in the intima at the early stage of human vein grafts [6].
Following endothelial death is cell regeneration, mononuclear
cell infiltration [7] and SMC accumulation which forms
arteriosclerotic lesions [8]. Although the vessel wall cells
contribute to lesion formation in graft atherosclerosis, which
is also called vascular positive remodelling, recent findings
demonstrated the major role of stem/progenitor cells in
the process [34]. Together, these findings strongly indicate
the contribution of stem or progenitor cells to vein graft
remodelling. The aim of this review is to provide an update
on the progress in this research field, highlight the role of
stem and progenitor cells in the pathogenesis of vascular
remodelling, and discuss the mechanisms of stem cell mobilization and homing to the vessel wall.
Endothelial progenitor cells
Accumulating evidence indicates the presence of EPCs
(endothelial progenitor cells) in the blood, which have the
capacity to proliferate and migrate as well as differentiate
into mature smooth muscle and endothelial cells [9–11]. EPCs
are characterized by the expression of CD34 and Flk1, two
antigens shared by embryonic endothelial progenitors and
haemopoietic stem cells [9]. The evidence from two research
groups indicates the existence of two types of circulating
endothelial cells. Approx. 5% of these circulating cells are
bone-marrow-derived EPCs originating from haemopoietic
stem cells, which are positive for CD34 and Flk1 [9,12]. A
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Figure 1 EPC-regenerated endothelial cells in vein grafts
Vessel segments were harvested from wild-type and Tie2-lacZ mice expressing the lacZ gene only in endothelial cells, and
prepared for en face staining with X-gal. Cross-grafting of vein segments between wild-type and Tie2-lacZ transgenic mice
indicates that the endothelium in the vessel wall was lost and regenerated by stem/progenitor cells.
large proportion of EPCs in blood originate from tissues
other than bone marrow [13,14]. Recently, it was demonstrated that Flk1+ cells derived from embryonic stem cells
can differentiate into both endothelial and SMCs [15], and
that progenitor cells in bone marrow of apoE-deficient mice
are significantly decreased during aging [16]. In humans,
the number of EPCs in blood is inversely correlated with
risk factors for coronary heart disease [10,17], e.g. smoking,
hyperlipidaemia and diabetes, highlighting the involvement
of these cells in cardiovascular diseases.
Stem/progenitor cells as source of lesional
cell accumulation in vein grafts
As described above, vascular endothelial cells in vein grafts
where biomechanical stress alters may have a higher rate of
death. It is a key issue to know how dead endothelial cells are
replaced and which cells are responsible for regenerating the
endothelium. Owing to a lack of appropriate animal models, it
has been difficult to answer these questions. To take advantage
of transgenic animals, we developed and characterized a new
animal model of vein graft atherosclerosis in wild-type [18]
and apoE-deficient [19] mice. The lesion displayed classical
complex morphological features and a heterogeneous cellular
composition. Furthermore, transgenic mice expressing lacZ
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gene promoters are now available. These mice express βgal (β-galactosidase) only in endothelial cells (TIE2-lacZ)
[20], SMCs (SM-lacZ) or all types of cells (ROSA26) [21].
When these mice are crossed with apoE-knockout mice,
which develop spontaneous atherosclerosis [22], then staining
the tissue with X-gal (5-bromo-4-chloroindol-3-yl β-Dgalactopyranoside) enables the detection of endothelial cell
origins in vein grafts. Using our animal models for vein
graft atherosclerosis [18,19], we performed vein isografts in
two types of transgenic mice expressing β-gal in endothelial
cells, including TIE2-lacZ, TIE2-lacZ/apoE−/− and wildtype mice. We demonstrated that the endothelium on vein
grafts completely disappeared due to apoptosis [5], and
was replaced by progenitor cells, of which approx. onethird of cells were derived from bone marrow cells [23].
Furthermore, the number of CD34+ and Flk1+ progenitor
cells in the blood of apoE-deficient mice were significantly
lower than those of wild-type controls, which coincided
with diminished β-gal+ endothelial cells on the surface of
vein grafts in TIE2-lacZ/apoE−/− mice [23]. These findings
indicated the contribution of progenitor cells to regenerate
damaged endothelium of the vessel wall (Figure 1).
Homing of EPCs to damaged vessels involving chemokines
was documented in animal models. One of them, the
Cardiovascular Bioscience
CXC chemokine SDF-1 (stromal cell-derived factor-1),
which is essential for stem cell mobilization/homing and
organ system vascularization [24–26], is highly expressed
in human atherosclerotic plaques and effectively activates
platelets in vitro [27]. Therefore a participation of SDF-1
in human atherothrombotic disease has been assumed. On
the other hand, NO is thought to be a key regulator in the
regulation of endothelial function and development of atherosclerosis. Notably, NO derived from eNOS (endothelial
nitric oxide synthase) and iNOS (inducible NOS) is essential
for the survival, migration and angiogenic response of
mature endothelial cells, and has been implicated in EPC
mobilization [28]. Recently, Mayr et al. [29] observed that
locally produced VEGF (vascular endothelial growth factor)
in vessels is significantly reduced in iNOS−/− mice, which
is related to decreased EPC attachment. It has been shown
that VEGF production in SMCs could be attenuated by
inhibition of NOS activity [30], indicating a relationship
between these two factors. NO was also shown to be involved
early on in angiogenesis, where inhibition of NOS activity
abolished the increase in capillary proliferation [31]. These
results demonstrated that NO is a key factor for VEGF
production in vascular SMCs stimulated by cytokines. Thus
NO, together with NO-induced VEGF, may synergistically
serve as chemokines for EPC homing and differentiation in
damaged vessels.
Once EPCs attach to the area of damaged endothelium,
they have to differentiate into mature endothelial cells in
order to acquire complete endothelial function. I hypothesize
that the direction of EPC differentiation can be determined
by local microenvironments, e.g. growth factors/cytokines
and haemodynamic forces. Yamamoto et al. [32] reported
that shear stress generated by blood flow or tissue fluid
flow can accelerate the proliferation, differentiation, and
capillary-like tube formation of EPCs derived from human
peripheral blood. Shear stress markedly increased the
EPC expression of VEGFR (VEGF receptor)/KDR (kinase
insert domain-containing receptor), ICAM-1 (intercellular
adhesion molecule 1) and VE-cadherin (vascular-endothelial
cadherin). The mechanisms of shear-induced progenitor
differentiation seem to involve several signal initiators and
transducers, as identified recently by Zeng et al. [33]. They
found shear stress can rapidly activate VEGFR–Akt–eNOS
pathways, in which Akt can also induce HDAC3 (histone
acetyltransferase 3) phosphorylation. One of the downstream
targets for HDAC3 is p53, which is up-regulated by shear
stress, and in turn activates p21. These mechanistic findings
for shear-stress-induced stem cell differentiation towards
endothelial cells could significantly enhance our knowledge
not only for understanding EPC differentiation but also for
searching new drugs to promote this process.
Smooth muscle progenitors in blood
It has been believed for a considerable time that the phenotype
of SMCs within neointimal lesions differs from medial cells,
i.e. contractile and secretory SMCs, which is known to be
essential for the migration and proliferation of SMCs in the
pathogenesis of arteriosclerosis. However, growing evidence
indicates that SMCs in the lesions may be derived from stem
cells [34]. Simper et al. [35] demonstrated for the first time
that smooth muscle progenitors were present in circulating
blood. They looked for these smooth muscle progenitors
in the human circulation by culturing mononuclear cells from
the peripheral circulation in a PDGF (platelet-derived growth
factor)-BB enriched growth medium. Concomitantly, a
recent report confirmed the presence of blood smooth muscle
progenitors that are derived from CD14/CD105-doublepositive cells [36]. Furthermore, they also investigated their
integrin profile to provide clues into the homing process of
these progenitor cells. Two studies by Simper et al. [35] and
Deb et al. [37] showed a distinct profile of these cells from
that of endothelial outgrowth cells. Both are in agreement that
the β1 integrin is present in greater quantities on smooth
muscle outgrowth cells in comparison with endothelial
outgrowth cells. The smooth muscle outgrowth cells also
showed a greater adherence to fibronectin, which is known
to be adhesive with β1 integrin. Further studies might allow
the targeting of β1 integrins in vivo and thus prevent differentiating progenitors from entering sites of arterial injury.
Smooth muscle progenitors in the
vessel wall
Tintut et al. [38] first identified a subpopulation of vascular cells derived by dilutional cloning of bovine aortic
medial cells, and showed that they undergo osteoblastic
differentiation and mineralization, which have the potential
to produce multiple lineages similar to mesenchymal stem
cells but with a unique differentiation repertoire. Moreover,
Hu et al. [39] found that the adventitia in aortic roots
harbours large numbers of cells containing stem cell markers
such as sca-1+ , c-kit+ , CD34+ and Flk1+ cells. Explanted
cultures of adventitial tissues displayed a heterogeneous
outgrowth, e.g. the formation of round-shaped cell islands
surrounded by fibroblast-like cell monolayers. Isolated
progenitor cells were able to differentiate into SMCs in
response to PDGF-BB stimulation in vitro. When progenitor
cells carrying the lacZ gene were transferred to the adventitial
side of vessel grafts in apoE-deficient mice, β-gal+ cells
were found in atherosclerotic lesions of the intima, and
enhanced the development of atherosclerotic lesions [39]. In
addition, a recent study demonstrated that healthy arteries
host progenitor cells in adult mouse, termed ‘arterial sidepopulation cells’, which represent approx. 6% of medial
cells [40]. In humans, a small number of progenitor cells
were identified within neointimal lesions and the adventitia
with variable expression of CD34, sca-1, c-kit and VEGFR2
markers, but no CD133 expression [41]. Thus vascular
progenitor cells exist within the vessel wall, and an increased
number of progenitor cells can be identified in the adventitia
of human vessels. These cells might be a source for the SMCs,
macrophages and endothelial cells that form atherosclerotic
lesions.
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Progenitor cell origins of lesional SMCs
Because of the availability of transgenic animals expressing
specific markers in the cells, the search for the evidence
of smooth muscle progenitors contributing to SMC accumulation in neointima was initiated almost simultaneously
by several groups [42–44]. One method for tracing and
distinguishing cells makes use of ROSA26 or GFP (green
fluorescent protein) mice expressing the lacZ or GFP gene
in all cell types. SM-LacZ mice, which only express the lacZ
gene in SMCs, also exist. Using such methods, researchers
have devised experiments to investigate the contribution of
smooth muscle progenitors in vein arteriosclerosis. Hu et al.
[42] provided the evidence that SMCs in the neointima were
derived from progenitor cells of both the vessel wall and
circulating blood.
Figure 2 Schematic representation of stem cells contributing to
vascular remodelling or arteriosclerosis
Endothelial cells covering the early neointimal lesions are derived
from EPCs, which have a shorter lifespan due to stimulation of locally
generated cytokines, free radicals and risk factors such as disturbed blood
flow, hyperlipidaemia and toxins. Functions, and differentiating abilities,
of progenitor cells may also be influenced by risk factors and local
environment resulting in ‘patch’ loss of endothelium. Smooth muscle
progenitor cells in blood may migrate into the lesions, whereas stem
cells present in the media and adventitia can migrate into the lesions
via the vasa vasorum. These cells differentiate into neo-SMCs within
arteriosclerotic lesions, which differ from medial SMCs. This process
repeats many times, leading to the formation of arteriosclerosis or
vascular positive remodelling.
The mechanisms of smooth muscle
progenitor recruitment
Similarly to the recruitment of other cells, chemokines
would be needed for progenitor cells to migrate into the
intima. PDGF-BB is recognized to be a chemokine for
SMCs in vitro and in vivo [45]. Using the in vitro Boyden
chamber assay system, we found that PDGF-BB has a
role in attracting sca-1+ progenitor cells derived from the
adventitia, suggesting that PDGF might serve as a chemokine
for vascular progenitors [39]. The second candidate protein
is SDF-1, which plays a key role in stem cell mobilization
and possibly in stem cell homing as well [46]. It has been
shown that SDF-1 binds to platelets at the site of injury,
triggers CXCR4 (CXC chemokine receptor)- and P-selectindependent arrest of progenitor cells on injured arteries
or matrix-adherent platelets, preferentially mobilizes and
recruits sca-1+ /PDGFR (PDGF receptor)-β + /lineage progenitors for neointimal SMCs without being required for
their differentiation [47]. Hence, the SDF-1–CXCR4 axis
is pivotal for vascular remodelling by recruiting a subset of
SMC progenitors in response to vascular injury, epitomizing
its importance for attracting smooth muscle progenitors from
circulating blood into the intima of the artery and vein grafts
[46].
Conclusion and perspectives
As described above, in response to endothelial damage, EPCs
may provide a circulating pool of cells that could form a
cellular patch at the site of lost endothelial cells, or serve
as a cellular reservoir to replace dysfunctional endothelium
covering vein graft neointimal lesions. Circulating EPCs
contribute to ongoing endothelial repair [10,17,48–50].
Furthermore, freshly attached EPCs or neo-endothelial
cells derived from blood may lack some of the mature
endothelial functions [34]. It may take several days or weeks
for these neo-endothelial cells to differentiate into mature
endothelium, during which LDL (low-density lipoprotein)
deposits in the intima, and blood mononuclear cells, including
smooth muscle progenitors, adhere to neo-endothelial cells,
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Authors Journal compilation migrate into subendothelial space, and take up modified LDL
to form foam cells (Figure 2). In this process, disturbed
blood flow in vascular grafts is a key factor influencing
EPC differentiation [34]. During endothelial injury and
replacement by EPCs, the vessel wall may also release
chemokines, e.g. PDGF-BB and SDF-1, which attract smooth
muscle progenitors from the blood as well as the vessel
wall via the vasa vasorum. These progenitor-derived neoSMCs within lesions are immature and produce inflammatory
cytokines, i.e. have a secretory phenotype and form foam
cells. Thus three major cell components, endothelial cells,
SMCs and macrophages, in arteriosclerotic lesions of vein
grafts are, at least in part, derived from stem/progenitors,
possibly from a common precursor such as the CD14
monocyte.
In summary, the introduction of new techniques has
provided a great amount of information at the cellular and
molecular levels during the last decade, hence expanding our
knowledge of the pathogenesis of arteriosclerosis or vascular
positive remodelling. Recent advances in vascular biology
namely with regard to the impact of progenitor cells in
lesion formation, has formed the basis for the hypothesis
presented in this article. By testing further the hypothesis of
vessel remodelling, emerging information should permit
Cardiovascular Bioscience
development of new diagnostic tools and strategies for
prevention and therapy of vascular disease.
I acknowledge all collaborators who have contributed to the work
summarized in the review. This work was supported by grants from
the British Heart Foundation and the Oak Foundation.
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Received 18 May 2007
doi:10.1042/BST0350895
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