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Transplantation of Endothelial Progenitor Cells as Therapeutics
for Cardiovascular Diseases
Huey-Shan Hung,*
1Woei-Cherng Shyu,*†
1Chang-Hai Tsai,‡§ Shan-hui Hsu,¶ and Shinn-Zong Lin*†#
*Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan †Graduate Institute of Immunology, China Medical University, Taichung, Taiwan ‡Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan §Department of Healthcare Administration, Asia University, Taichung, Taiwan
¶Department of Chemical Engineering and Institute of Biomedical Engineering, National Chung Hsing University, Taichung, Taiwan #China Medical University Beigang Hospital, Yunlin, Taiwan
With better understanding of endothelial progenitor cells (EPCs), many therapeutic approaches to cardiovas-cular diseases have been developed. This article will review novel research of EPCs in promoting angiogen-esis, vasculogenangiogen-esis, and endothelialization, as a design for future clinical treatment. Cell therapy has the potential to supply stem/progenitor cells and multiple angiogenic factors to the region of ischemia. The efficacy of EPC transplantation may be impaired by low survival rate, insufficient cell number, and impaired function in aging and diseases. Combination of EPCs or cells primed with growth factors or genetic modifi-cation may improve the therapeutic efficacy. The molecular mechanism involved in EPC repairing processes is essential. Thus, we have also addressed the molecular mechanism of mobilization, homing, and differentia-tion of EPCs. The potential of therapeutic neovascularizadifferentia-tion, angiogenic factor therapy, and cell transplanta-tion have been elucidated. Based on past experience and actual knowledge, future strategies for EPC therapy will be proposed in order to fully exploit the potential of EPC transplantation with clinical relevance for cardiovascular disease applications.
Key words: Endothelial progenitor cells (EPCs); Cardiovascular diseases; Angiogenesis; Cell therapy
INTRODUCTION In response to ischemic injury, EPCs are mobilized from the bone marrow. The infusion or injection of stem or progenitor cells has been shown to improve neovas-Cell therapy is currently attracting growing attention
as a potential issue of improving the prognosis of pa- cularization and heart function after ischemia in various experimental studies and clinical trials (46,52,106). tients with cardiovascular diseases (22,52,77,97,113).
Cell-based therapy to stimulate postnatal vasculogenesis EPCs can migrate to the site of blood vessel injury to help repair the damage and to differentiate into mature or to repair the integrity is being evaluated for
cardio-vascular diseases with excess morbidity and mortality, endothelial cells (37). Therefore, it can be therapeuti-cally useful for treating ischemic injury. Studies have including the ischemic heart disease, in-stent restenosis,
pulmonary hypertension, and peripheral arterial occlu- described reduced EPC numbers in diabetic patients who suffered a stroke (115). A report also indicated that EPC sive disease (3,39,79). To date several clinical studies
have suggested the potential efficacy of several different number correlated with the level of stromal derived fac-tor-1 (SDF-1) from patients with the coronary disease or cell types (6,67,77,79). Endothelial progenitor cells (EPCs)
have been studied as a novel tool to assess the severity ischemic cardiomyopathy (33). Because EPCs are in-volved in neovascularization, enhancing the number of cardiovascular disease and as a new strategy in
regen-erative medicine (21,77,113). and/or activity of EPCs could improve the recovery of
Online prepub date: June 22, 2009.
1These two authors contributed equally to this article.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. Tel: 886-4-22052121; Fax: 886-4-220806666; E-mail: [email protected] or Shan-hui Hsu, Ph.D., Department of Chemical Engineering, National Chung Hsing University, Taichung, Taiwan. Tel: 886-4-22852317; Fax: 886-4-22864734; E-mail: [email protected]
patients who experience ischemic injury. They might body-coated stent have been evaluated as a replacement to currently available drug-eluting or bare metal stents also be useful as autologous vectors for delivering genes
to sites of vascular growth in regenerating tissues (59). (63). The treatment with G-CSF, which mobilizes EPCs from bone marrow, can safely improve the clinical out-Applications associated with cardiovascular diseases
depend on the functional activity of EPCs (39,77,115). comes of patients with atherosclerotic peripheral artery disease (PAD) (83). Moreover, implantation of EPCs EPCs from type II diabetes patients exhibit impaired
proliferation, adhesion, and reduced angiogenic potential and bone marrow cells may result in increase in athero-sclerotic plaque size and composition in apolipoprotein in vitro (26). Similar functional alterations have been
indicated in EPCs isolated from aged patients with coro- E knockout mice (30). Besides, the obvious therapeu-tical potential of blood-derived progenitor cells in pa-nary artery disease or ischemic cardiomyopathy (35,47).
However, controversial issues on EPC phenotypes, ori- tients indicates that the application is safe, feasible, and may improve both functional and clinical indices with gins, and functions of endothelial repair still exist. For
example, the potential limitation for cell therapy is a low peripheral arterial occlusive disease and critical limb is-chemia (48). Additionally, the ability of G-CSF to mobi-rate of engraftment and persistence of cells in the
ische-mic tissue. lize functional EPCs in patients with coronary artery dis-ease has been tested in a clinical trail (1,74,104). The present review focuses on the role of EPCs in
repairing the vessel wall during the development of car- Evidence showed that the transplantation of EPCs re-sulted in a significant increase in myocardial viability diovascular disease. We address the recent
develop-ments in EPC functionality for cell therapy and the effi- and perfusion (4,23). Alteration in progenitor cell proan-giogenic function may participate to the hypertension-ciency of EPCs on the maintenance of endothelial
integrity, endothelialization, and angiogenesis from in induced impairment in postischemic revascularization (111). When systemically applied, spleen-derived mouse vitro to in vivo study after cell transplantation.
mononuclear cells (MNCs) and EPCs home to the site
CLINICAL TRIALS OF EPC THERAPY of vascular injury, resulting in enhanced reendothelializ-IN CARDIOVASCULAR DISEASES ation associated with decreased neointima formation
after angioplasty (101,102). Alternatively, the enhanced Much evidence has shown that EPCs may be a
valu-able tool for clinical health providers (25,55,80). Impor- regenerative activity of EPCs by human telomerase re-verse transcriptase transfer will provide novel therapeu-tantly, EPC function and number now have been highly
correlated with the risk of cardiovascular disease (7,57). tical strategies for postnatal neovascularization in severe ischemic disease patients (65). Indeed, ex vivo expanded A recent study showed that the level of circulating EPC
expression level predicted the occurrence of cardiovas- EPCs can incorporate into the foci of myocardial neo-vascularization and have a favorable impact on the pres-cular events and vaspres-cular tissue injury (2). Interestingly,
a study indicated that the increased number and func- ervation of left ventricular function (45). tionality of EPCs may be achieved by targeted
pharma-THE TRANSPLANATION OF EPCs
cological strategies alone (85) or in combination with
FOR DISEASE IN ANIMAL MODELS
proangigenic cytokines (17). Other factors can affect the
function of EPCs, such as angiotensin II, glucose, and It is important that the damaged endothelial cells have to be replaced by the adjacent intact endothelium low density lipoprotein (30,53,110). Therefore, EPCs
exhibit an important role in endothelial cell regenera- for vessel regeneration (88). Stem cells can differentiate into a variety of cells to replace dead cells or to repair tion, which may be a benefit in repair of cardiovascular
disease (15,89,93). Recently, experimental studies and damaged tissues. Recent evidence indicates that stem cells are involved in the pathogenesis of transplant arte-early phase clinical trials tended to support the concept
that cell therapy may enhance cardiovascular repair (24). riosclerosis (28). Several studies have highlighted that the increase in the number of circulating progenitors, In addition, intramyocardial VEGF-A165 gene transfer
followed by bone marrow stem cell mobilization with induced by cell transfusion or enhanced mobilization, can also enhance restoration and integrity of the endo-granulocyte colony-stimulating factor (G-CSF) seemed
to be safe in improving the homing of stem cells and thelial lining, suppress neointimal formation, and in-crease blood flow to ischemic sites (5,87).
inducing angiogenesis in patients with severe chronic
is-chemic heart disease (76). In patients, the number of EPCs is poorly correlated with the severity of atherosclerosis (36). Indeed, in vari-Studies have also suggested that the implantation of
endothelial progenitor cells could be safe and effective ous animal models, transplantation of bone marrow-derived progenitor cells could sufficiently rescue organ function for achievement of therapeutic angiogenesis for patients
with limb ischemia (107). In an alternate study, percuta- and enhance vascular repair and tissue regeneration (16,49,90). The incorporation of circulating EPCs into neous coronary intervention utilizing a new EPC
anti-the vessel wall was observed in animal model (28,90). zation, homing, and differentiation of EPCs in vascular diseases.
In another model of transplantation, it was found that
the endothelial monolayer in a vein graft postsurgery In most studies, many biochemical factors such as growth factors (SDF-1, G-CSF, GM-CSF, FGF, PIGF) was completely lost and subsequently replaced by
circu-lating EPCs (61). These progenitor cells can improve (44,56,70,104), cytokines (IL-12, IL-3, IL-6, IL-8, and IL-1β) (43,71,81), erythropoietin (EPO) (101,103), angi-vascular repair and reduce angi-vascular injury.
An important report indicated that the intravenous in- opoietin-2 (94), and heme oxygenase-1 (HO-1) (58) that are well known to mobilize human stem cells have been fusion of spleen-derived mononuclear cells seemed to
improve the endothelium-dependent vasodilatation in found to increase the number of EPCs in arterial remod-eling during ischemic damage. An increase in the num-atherosclerotic mice (101). It is thus more convincing
that progenitor cells play an important role in repairing ber of circulating progenitor cells, induced by cell trans-fusion or enhanced mobilization, can also enhance the the vascular injury (60,102). In addition, EPCs derived
from spleen homogenates also enhanced reendothelializ- restoration and integrity of the endothelial lining, sup-press neointimal formation, and increase the blood flow ation and reduce neointima formation after induction of
endothelial cell damage using the carotid artery animal to ischemic sites (8,31,72,98). However, the beneficial outcome of EPC infusion depends on the growth and model (102). Besides, rapid repair of the endothelium
with reduced activation of smooth muscle cells and neo- differentiation factors within the tissue, cell-to-cell inter-actions, and the degree of injury (75,112).
intima formation has been found in vivo after the
im-plantation of EPCs using a ballon injury model (68,105). Experimental studies have provided novel options for improving survival and function by transduction of stem The transplantation of EPCs into mice after balloon
in-jury could induce endothelial nitric oxide (eNOS) over- or progenitor cells with prosurvival genes (e.g., Akt or telomerase) (18,38,78). Pretreatment of cells with small expression and accelerate the endothelial repair (96). In
an alterative study, EPCs reduced the proinflammatory molecules, such as statins, p38 inhibitors, or endothelial nitric oxide synthase (eNOS) enhancers, has been used properties and the IL-10 expression in the
atherosclero-sis plaque site in mice model (19). to enhance cell homing, migration, and functional recov-ery after the induction of ischemia (18). Several studies The infusion of EPCs or isolated hematopoietic
pro-genitor cells promotes neovascularization of ischemic have shown that the prosurvival phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway may play an important role myocardium and improves the ventricular function after
myocardial ischemia in both human and animal study in endothelial cells and EPCs (20,114). Thus, statins, VEGF, EPO, estrogen, and shear stress have also been (40,62,69). In a canine model, circulating endothelial
progenitor cells could be a substitute source of endothe- also reported to modulate the PI3K/Akt pathway (20,27, 41,51,86,100). Recently, the increased number of EPCs lial cells for endothelialization on small-diameter-vessel
prostheses to ensure nonthrombogenicity (109). A novel and enhanced neovascularization through an eNOS-dependent pathway were also reported. The activity of hybrid cell-gene therapy based on the phagocytosing
ac-tion of EPCs was explored as a new therapeutic strategy eNOS is essential for ischemic remodeling, and to mobi-lize EPCs and even modulate the neurogenesis in brain. for the treatment of pulmonary hypertension (66).
Alter-natively, a possible role of SDF-1 in the homing of stem Besides, reports also addressed that eNOS improved an-giogenesis and cerebral blood flow in the stroke animal cells to damage areas has been noted in the animal
mod-els of liver, limb, heart, and brain injury (42,64,95,108). model (13,14). Increased nitric oxide (NO) availability is required for the statin-induced mobilization of EPCs Overall, it seems that proper mobilization of EPCs may
lead to the repair of vascular injury. The application of (73). NO produced by eNOS also correlates with SDF-1 and the CXCR4 signaling pathway to induce the mobi-endothelial progenitor cells on various cardiovascular
diseases is summarized by Figure 1. lization and homing of EPCs (114).
Although the importance of SDF-1 in stem cell
re-MECHANISM UNDERLYING cruitment to the injured tissue is well established, the THE THERAPEUTIC EFFECTS underlying mechanism of SDF-1 in ischemic tissue still OF ENDOTHELIAL PROGENITOR CELLS needs to be elucidated. Furthermore, SDF-1 gene
ex-pression is regulated by the transcription factor hypoxic-As highlighted by several reports, the functional
re-pair properties of EPCs derived from different sources, inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tis-including bone marrow and non-bone marrow organs
such as the spleen, may vary with the maturation state sue (44). SDF-1 is the only chemokine family member known to be regulated by HIF-1 (10). It seems reason-of the cells (112). Thus, understanding the molecular
mechanisms involved in EPC-repairing processes is es- able that HIF-1-regulated SDF-1 expression may be im-portant in a number of regenerative pathways. Thus, ex-sential. Here, we will review the mechanism for
mobili-Figure 1. Schematic representation of the endothelial progenitor cells as therapeutics for cardiovas-cular diseases.
pression of HIF-1 activity may be a useful approach to cules in the recruitment of EPCs to ischemic tissue. The knowledge may provide novel opportunities for clinical improve the regenerative potential after ischemic injury
(44). Integrins are crucial transmembrane molecules that cardiovascular disease applications. A summary of the possible mechanisms between EPCs and cardiovascular mediate cell adhesion, migration, and the homing of
pro-genitor cells such as EPCs to ischemic tissue, possibly disease is shown in Figure 2. through the enhanced angiogenesis by homing stem cells
FUTURE EXPLORATION
(54). The β2-integrins are involved in the homing of
EPCs to the site of ischemia and are essential for their Cell-based transplantation strategies have the poten-tial to become a major therapeutic advance for cardio-neovascularization capacity in vivo (11). The activation
ofβ2-integrin on EPCs has been shown to significantly vascular disease. There are still controversial issues re-garding the active potency of EPCs for proliferation, improve the neovascularization capacity in vivo in a
model of hindlimb ischemia (9). Whether integrins play differentiation, and migration in vitro, therapeutic neo-vascularization and reendothelialization in vivo of the an important role for the mechanism of repair in
cardio-vascular disease remains to be determined in the future. EPC-based treatments. Although available clinical stud-ies of EPC transplantation show beneficial results in Besides, further studies are still required to elucidate
re-modeling after myocardial infarction (91), these studies the clinical trail of EPCs. EPCs are relatively rare cells, and expansion of sufficient number of a definite subpop-still encounter some difficult issues that need to be
solved in the future. ulation from peripheral blood is hardly possible. Addi-tionally, the therapeutic implantation is associated with Clear characterization of the specific subpopulation
of stem/bone marrow cells that have the most beneficial a change in phenotype and differentiation and the risk of cell biology, and may need other activation or stimu-properties is important for vascular repair (12,29,32). Thus,
it is also necessary to develop a safe protocol and hope lation (50,99). Besides, the ability and functional proper-ties of EPCs in aging adults are really limited, especially to isolate sufficient numbers of EPCs that can
continu-ously maintain their angiogenic potential and be used in those with cardiovascular disease where a further re-duction of EPCs was shown (82,92).
to treat patients in clinical trails with damaged vascular tissues. Ideally, a specific cell population or combination
CONCLUSION
needs to be accurately determined. It is important to note
that most preclinical and clinical studies testing the ther- Stem cell therapy is feasible, moderately effective, and does not expose patients to high risk. The therapeu-apeutic effects of EPCs were based on introducing either
whole bone marrow cells or a crude bone marrow cell tic effects of EPCs are well performed in several studies, but there are things remaining obscure. A combined cell population containing EPCs, hematopoietic cells, and
ir-relevant pluripotent cells, with some animal experiments therapy comprising EPCs is also a promising option, but issues regarding the types of patients, the types of used using purified “EPCs,” such as CD34+ hematopoietic
stem cells (HSCs) (34,84). cells, and the therapeutic outcomes all complicate the wide use of cell therapy. There is also the necessity of Alternatively, a major problem was also observed in
Figure 2. Possible molecular mechanism between EPCs and cardiovascular diseases. VEGF, vascular endothelial growth factor; G-CSF, granulocyte colony-stimulating factor; FGF, fibroblast growth factor; PIGF, placenta growth factor; HGF, hepatocyte growth factor; SDF-2, stromal derived factor 1; IL-1β, interleukin-1β; IL-3, -6, -8, interleukin-3, -6, -8; TNF-α, tumor necrosis factor-α; eNOS, endothelia nitric oxide synthase; NO, nitric oxide; CRP, C-reactive protein; LDL, low density lipoprotein; EPO, eryothropietin; HIF-1, hypoxia inducible factor.
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Scharffetter-complex process. Future studies should also explore the
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