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PII S1050-1738(07)00176-4 TCM

Stem Cell Therapy for Vascular DiseaseBenjamin Adams, Qingzhong Xiao, and Qingbo Xu⁎

Endothelial dysfunction/loss is a key event in the development ofvascular diseases, including native atherosclerosis, angioplasty-inducedrestenosis, transplant arteriosclerosis, and vein bypass graft athero-sclerosis. In challenge to the traditional concept that lost endothelialcells were replaced by neighboring endothelial replication, recent studieshave shown that stem cells in blood and the vessel wall have the abilityto repair endothelial cells after extensive loss. Concomitantly, accumu-lating data indicate that stem cell therapy is a promising option for thetreatment of vascular diseases and might, in the future, contribute totissue regeneration, that is, the restoration of endothelium lining thearteries to recover the function of the vascular system. In the presentreview, we will focus on the progress of stem cell therapy, discuss themechanisms of stem cell differentiation into endothelial cells, and pointout the clinical potential of stem cell therapy in the future. (TrendsCardiovasc Med 2007;17:246–251) n 2007, Elsevier Inc.

� Introduction

Vascular disease is a broad term encom-passing any condition which affects thevascular system, including hyperlipide-

mia-induced (native) atherosclerosis,angioplasty-induced restenosis, trans-plant arteriosclerosis, vein bypass graftatherosclerosis, and aneurysms. Dysfunc-tion of the endothelium is thought to beoneof the earliest abnormalities that leadsto atherosclerosis and is intimately relatedto modifiable risk factors such as highcholesterol levels, high blood pressure,smoking, and diabetes (Ross 1999). Forprevention and therapy of the disease,current awareness of the need for ahealthy lifestyle and diet rich in vegetablesand fruits, and giving-up smoking, forexample, has gone a longway to positivelyinfluence this disease. Furthermore, med-

Benjamin Adams, Qingzhong Xiao, andQingbo Xu are at the Cardiovascular Division,King's College London, SE5 9NU London, UK.

⁎ Address correspondence to: Prof. QingboXu, Cardiovascular Division, King's CollegeLondon, James Black Centre, 125 ColdhabourLane, London SE5 9NU, UK. Tel.: (+44)2078485295; fax: (+44) 2078485296;e-mail: qingbo.xu@kcl.ac.uk.

© 2007, Elsevier Inc. All rights reserved.1050-1738/07/$-see front matter

ications such as statins, calcium-channelantagonists, and antiplatelet agents havebecome common, as well as significantstrategies to treat vascular disease orarteriosclerosis (Katz et al. 2007). How-ever, cardiovascular disease remains amajor contributor to humandeath despitefurther advancements in treatments, suchas thrombolysis and angioplasty. With theimplementation of primary angioplastyfor occluded vessels, a shift seems to haveoccurred from people dying during theacute phase of a heart attack to thoseeventually dying from the resultant long-term effects, namely, restenosis-relatedheart disease. There has consequentlybeena search fornew therapies for vasculardisease, which can try to overcome currentproblems such as instent restenosis.

Stem cell therapy is a promisingoption for the treatment of vasculardiseases. As a source of stem cell therapy,there are three types of cells which arecategorized according to their origins,that is, derived from early embryonicbodies, adult tissues or umbilical cordblood (Anversa et al. 2007). Stem cells areundifferentiated cells that can developinto any type of cells in the body,including endothelial and smooth mus-cle cells (Margariti et al. 2006). Recentstudies have shown that endogenous(adult) stem cells have the ability torepair endothelial cells which have beenlost or damaged following balloon angio-plasty or surgical vein grafting, therebyrestoring the integrity of the vessel and,most importantly, its function (Xu 2006).It is this concept which has generated agreat amount of high-profile publicity forthe use of stem cells as a tool fortherapeutic intervention in vascular dis-ease. However, one potential limitation

TCM Vol. 17, No. 7, 2007246

for the use of autologous cells is thedocumented decline in the number andfunction of stem cells in patients. Thisoutcome is seen particularly in patientswith coronary artery disease, diabetes,and severe heart failure (Seeger et al.2007). In the present review, we willfocus on the application of stem cells totreat vascular disease, to discuss themechanisms of stem cell differentiation,to compare the use of both embryonicstem cells (ESCs) and adult stem celltherapy, and to point out the limitationsof stem cell therapy.

� Embryonic Stem Cell Therapy

Embryonic stem cells are a promisingsource of “pluripotent” stem cells, andaccumulating evidence indicates thatESCs can differentiate into both vascularendothelial and smooth muscle cells(Levenberg et al. 2002). Differentiation ofESCs toward the endothelial lineage is animportant step in vasculogenesis and canbe induced experimentally in vitro. Toobtain a large number of high qualityendothelial and smooth muscle cells fromESCs, recent investigation focused on themechanistic study of stem cell differentia-tion (Xiao et al. 2006). Investigators aretrying to understand which stimuli and/orenvironment are required for ESC differ-entiation and what are the signal path-ways leading to stem cell differentiationinto vascular cells. So far, two factors thatinitiated such a differentiation are vascu-lar endothelial growth factor (VEGF) andmechanical force generated by the intrin-sic flow of blood, such as laminar shearstress (Wang et al. 2005, Zeng et al. 2006).It was reported that VEGF and/or shearstress significantly induces expression ofendothelial cell-specific markers such asCD31, von Wilbrand factor, and VE-cadherin, together with a distinct mor-phologic effect, changing the cells from afibroblast-like appearance to a more cob-blestone shape (Wang et al. 2005). Inter-estingly, laminar flow also appears toactivate the molecular pathways, whichlead to histone modifications includingthe stabilization and activation of histonedeacetylases (HDACs) (Illi et al. 2005,Zeng et al. 2006). Embryonic stem cellsundergo complex gene-specific and func-tionally important remodeling of chroma-tin structure necessary for differentiationinto endothelial cells. Overexpression ofthe HDAC3 isoform has been shown to

increase protein levels of endothelial celllineage-specific markers in VEGF-induced endothelial differentiation.Furthermore, we also provide evidencethat shear or VEGF stimulation activatesHDAC3 by posttranslation stabilizationthrough Flk-1-PI3K-Akt signal pathways,thus providing mechanistic aspects forshear-induced stem cell differentiationtoward endothelial cells (Zeng et al. 2006).

After understanding the mechanismsof ESC differentiation, further classifica-tion of the surface markers for vascularprogenitors is an important issue forESC-derived cell therapy. Difficulty in prepar-ing pure populations of cell lineages, suchas Flk-1+ cells, has hampereddissection ofthe mechanisms underlying vascular for-mation (Yamashita et al. 2000), althoughthe ability to produce the cells with highpurity through flow cytometry sortingtechniques appears to be promising.However, it is difficult to obtain a largenumber of cells with high purity for celltransfer studies. Our previous datashowed that stem cell antigen-1 (Sca-1)can be used as a sorting marker ofvascular progenitors to isolate these cellsfrom adult adventitial tissues (Hu et al.2004). After intensive searching, wedemonstrated that Sca-1+ progenitorsisolated from ESC cultures could serveas common vascular progenitors for bothendothelial and smooth muscle cells(Xiao et al. 2007, Xiao et al. 2006).Embryonic stem cell-derived endothelialcells can form capillary-like networks onMatrigel (Becton, Dickenson, Bedford,MA) in vitro and vascular-like structureswithin Matrigel plugs in vivo, whichindicate that these cells have endothelialfunctions (Figure 1).

Angioplasty is routinely used in clin-ical practice to treat patients with severeatherosclerosis, but restenosis occursafter a period of time owing to loss ofendothelium resulting in smooth musclecell accumulation in the intima (Grayand Sullivan 1996, Kuntz 1999). Expo-sure of the subendothelial matrix pro-teins to blood, following balloonangioplasty and stenting, is a risk forthrombus formation and subsequentsmooth muscle cell proliferation leadingto luminal narrowing and recurrence ofsymptoms. If the damaged endotheliumcan be restored quickly, a reduction instent thrombosis and reocclusion wouldbe seen. When these ESC-derivedendothelial cells were locally trans-

planted into an injured mouse artery,they were found to form neoendotheliumthat covered the injured areas. This celltransplantation resulted in a significantdecrease in neointimal lesions 2 weeksafter injury. Thus, local transfer of ESC-derived endothelial cells has been shownto have a striking beneficial effect onreendothelialization after wire-inducedarterial injury (Figure 1), regeneratingthe endothelium and reducing neointi-mal lesion formation (Xiao et al. 2006).On the other hand, immune rejection bythe host immune system has been con-sidered to be one of the greatest hurdlesfor cellular transplantation in humans.However, recent data support the con-cept that human ESCs and/or theirdifferentiated derivatives possess immune-privileged properties, suggesting that cellsderived from human ESC may provide apotential tool for induction of immuneto-lerance (Menendez et al. 2005).

� Endothelial Progenitor CellTherapy

Endothelial progenitor cells (EPCs)form a population of cells existing inperipheral blood mononuclear cellswhich share a similar profile of commonantigenic determinants to that of adultstem cells (Urbich and Dimmeler 2004).The ability of these cells to incorporateinto sites of active neovascularizationwas an enormous step forward in stemcell biology as the use of autologous, orpatient-derived, stem cell therapybecame a real possibility. However, acritical limitation for EPC-based strate-gies progressing to therapeutic applica-tions is their low number in thecirculation, reflecting the seeminglyinsufficient quantity of endogenousEPCs to overcome vascular “insults”above a certain threshold. There havebeen a number of ways proposed to tryand overcome this problem. First, it canbe achieved by increasing the number ofcirculating EPCs through pharmacologicmobilization with growth factors, suchas granulocyte colony-stimulating factor(G-CSF), activating progenitor cellreleasing factors to release the stemcells from the bone marrow into thecirculation (Kong et al. 2004). Initialanimal experiments with G-CSF pretreat-ment before vascular injury seemed to bepromising, finding enhanced reendothe-lialization and decreased neointimal

247TCM Vol. 17, No. 7, 2007

formation (Kong et al. 2004, Yoshioka etal. 2006). However, the nonselectivenature of G-CSF in the mobilization ofEPCs, showing also increased migrationand proliferation of smooth muscle andinflammatory cells, perhaps contributedto the significant instent restenosis rateseen in the Myocardial Regeneration andAngiogenesis in Myocardial Infarctionwith G-CSF and Intra-Coronary StemCell Infusion clinical trial (Kang et al.2004, Kang et al. 2006). These concernswere not substantiated with subsequentquantitative coronary angiography stu-dies (Assmus et al. 2006) and additionalintracoronary ultrasoundmeasurements,although the timing of G-CSF treatmentvaries between these studies. Conse-quently, the number of circulatinginflammatory cells at the time of stentimplantation seems to be directly relatedto the degree of subsequent neointimalformation (Kang et al. 2006).

The second way of increasing thenumber of endogenous EPCs is to harvestmononuclear cells from the peripheralblood or hematopoietic tissue beforein vitro differentiation to endothelial cellsand/or tissue culture expansion. The cellscan then be transfused back to the patienteither systemically or locally at the time ofangioplasty. A more global improvementin endothelial function was seen with

systemic transfusion of vascular progeni-tor cells in the study by Wassmann et al.(2006). Intravenous transfusion of spleen-derived mononuclear cells, isolated fromwild-type mice, on 3 consecutive dayssignificantly restored and improvedendothelium-dependent vasodilatation inapolipoprotein E−/− mice fed a high-cholesterol diet. Intravenously transfusedEPCs, cultured from spleen-derivedmononuclear cells, were found to home

to the site of injury in a mouse modelcausing enhanced reendothelializationand associated reduced neointima forma-tion (Werner et al. 2003). Furthermore, inthis study, intravenously transfused cellswere exclusively found at the injury sitewhen homing to the host organ wasprevented by splenectomy. If the prefer-ential homing to the spleen could be

Figure 2. Endothelial progenitor cell (EPC) origins. EPCs could be released from bone marrow,adipose tissues, vessel wall–especially adventitia–and spleen into blood, where they express c-kitand Sca-1 antigens at the early stage, and then CD34/Flk-1. Circulating EPCs can repairdamaged vessels and also be isolated and expended for cell therapy.

Shear/VEGF treatment

Stem cells in vitro

Isolation of sca-1+ progenitors

Apply the cells to denuded artery

Endothelial phenotype

A B C

Figure 1. Stem cell-based therapy for injuredvessels. Shear stress or VEGF treatmentresults in ESC differentiation into Sca1+progenitors, which were isolated with mi-crobeads. These cells were applied to injuredarteries locally resulting in reduced thelesion formation. (A) Uninjured artery. (B)Injured artery without cell treatment. (C)Injured artery with Sca1+ cell treatment.(Zeng et al. 2006).

Stem cells

Neo-SMCs

Media

Adventitia

Vasa vasorumStem cells

Figure 3. Schematic representation for stemcells to participate in the formation ofarteriosclerosis. Stem cells and progenitorsexisting in blood can repair damaged en-dothelial cells and penetrate/deposit into theintima. Meanwhile, angiogenesis withinatherosclerotic lesions occur because lesionsbecome enlarged, creating a hypoxic environ-ment. These microvessels or vasa vasorumplay a part in transport vascular stem orprogenitor cells from the media and adventi-tia into the lesion. These cells differentiateinto neo-smooth-muscle cells within the ves-sel. This process repeats many times, leadingto the formation of arteriosclerotic lesions.

TCM Vol. 17, No. 7, 2007248

“switched off” in some way in humans,thereby prolonging the circulating time ofEPCs, this may result in the enhancedhoming of these cells to the site of injury inclinical practice (Figure 2).

Perhaps the most exciting applicationof this work is the local application ofbonemarrow stemcells, withhigh-profileclinical trials such as the Reinfusion ofEnriched Progenitor Cells and InfarctRemodeling in Acute Myocardial Infarc-tion trial (Schachinger et al. 2006) and,more recently, the UK stem cell founda-tion-funded “heart repair project.” In thelatter trial, patients directly receive theirown stemcells (harvested from their bonemarrow) as a direct intracoronary trans-fusion within 5 h of the initial “heartattack.” It is believed that this is theoptimal time for the procedure, and it ishoped that stem cells used in this way canimprove quality of life and delay, orprevent, the onset of heart failure byrepairing damaged endothelial cells. Thefinal 1-year results of the former Reinfu-sion of Enriched Progenitor Cells andInfarct Remodeling in Acute MyocardialInfarction trial indicate that intracoronayinfusion of enriched bone marrow cellswas associatedwith improved recovery ofglobal ventricle contractile functionwithin 4 months, associated with a sig-nificant reduction of the occurrence ofmajor adverse cardiovascular events afteracute myocardial infarction (Osterziel2007, Schachinger et al. 2006). However,a negative result by using bone marrowcells to patients after myocardial infarc-tion was reported as well (Lunde et al.2006). For these studies, we should keepin mind that the cells used are nonse-lected bonemarrow cells that contain notonly EPCs but also other types of stemcells, that is, mesenchymal stem cells.Nevertheless, a recent pilot study indi-cates that intravenous infusion of auto-logous EPCs seemed to be feasible andsafe and might have beneficial effects onexercise capacity and pulmonary hemo-dynamics in patients with pulmonaryarterial hypertension (Wang et al. 2007).

In vessel graft models, our group hasshown that a large number of endothelialcells in the grafted vessels undergo apop-tosis or necrosis during the first few daysafter surgery followed by endothelialregeneration (Mayr et al. 2000, Xu et al.2003). In a study of transgenic micewhich had vein grafts carrying LacZgenes driven by an endothelial TIE2

promoter, a vein fragment from TIE2–LacZ was grafted into the carotid arteryof wild-type mice. The number of β-gal+

cells subsequently diminished until thefourth week, when none were present,suggesting recipient stem cell origins ofendothelial cells. Similarly, it was alsodemonstrated that endothelial cells inallograft arteries were replaced by reci-pients cells, indicating a contribution ofcirculating EPCs to complete endothelialrepair (Hu et al. 2003). Recently, Mayret al. (2006) observed that locally pro-duced VEGF in vessels is significantlyreduced in inducible nitric oxide (NO)synthase−/− mice, which is related todecreased EPC homing. These resultsdemonstrated that NO is a key factor forVEGF production. Together with VEGFin the vessel wall, NOmay synergisticallyserve as chemokines for EPC homing anddifferentiation in repairing damaged ves-sels, suggesting an alternative way toenhance stem cell repair.

� Other Sources of Stem Cells

Recently, several groups reported thepresence of vascular progenitor cells ina variety of tissues, including the adven-titia of the arterial wall (Hu et al. 2004),spleen (Wassmann et al. 2006), liver(Aicher et al. 2007), and adipose tissues(Lin et al. 2006, Planat-Benard et al.2004, Prunet-Marcassus et al. 2006).Early studies from our laboratorydemonstrated that a significant propor-tion of EPCs engrafted into the damagedvessel wall of vessel grafts was derivedfrom non-bone marrow tissues (Hu et al.2003, Xu et al. 2003). Interestingly, arecent report from Aicher et al. showedthe contribution of circulating cells fromnon-bone marrow sources to the vascu-lature by using a parabiosis model withor without reverse bone marrow trans-plantation (Aicher et al. 2007). Theyprovided evidence for the mobilizationof tissue resident c-kit+CD45− progenitorcells that have the capacity to incorpo-rate into the vasculature of ischemictissue. These findings implicate thatother sources of progenitor cells maysignificantly contribute to vascularrepair and may serve as additionalsources of stem cell therapy (Figure 2).

Other approaches to overcome theproblem of low numbers of EPCs in theperipheral circulation include the use ofhuman umbilical vein blood. Umbilical

cord blood contains up to 10-fold highernumbers of EPCs than in the adult and inaddition, cord blood cells have a greaterproliferative capacity (Kalka et al. 2000).Tissue-resident progenitor cells such asthose in adipose tissue could also pose apromising source for cell-based thera-pies. The key benefits of using pluripotentadipose cells for autologous cell therapyis clearly the ease with which they can beharvested and their relative abundance.Although some reports showed the use-fulness of adipose tissue-derived vascularprogenitors in angiogenesis (Lin et al.2006, Planat-Benard et al. 2004, Prunet-Marcassus et al. 2006), data concerningalternative sources of stem cells to treatthe vascular disease is still lacking.

� Tissue-Engineered Vessels

The idea of using stem cells to construct acompletely tissue-engineered vessel hasexisted for a small period and is realisti-cally supported by the findings that stemcells may be the main source of endothe-lial and smooth muscle cells in arterio-sclerotic vessels. Traditionally, it isbelieved that the accumulation of neointi-mal smoothmuscle cells was attributed tocellmigration from themedia.However, itis now known that there are multiplesources of lesional cells, including stemcellswhich are present in peripheral bloodas well as the adjacent adventitia of thevessels (Xu 2006). This is an importantconcept, as it suggests that there is a lackof appropriate negative feedback in thehealing artery, resulting in exuberantneointimal proliferation. Therefore, stemcell-derived vascular cells can construct a“native” vessel or remodel a grafted vesselin vivo (Hu et al. 2002), providing a solidsupport for producing a vessel by usingstem cells (Figure 3).

Vascular bypass grafting is a commonlyperformed procedure to replace blockedvessels for ischemic heart disease andperipheral vascular disease (Campbelland Campbell 2007). However, manypatients do not have healthy vesselswhich are suitable for the replacementprocedure (Hoenig et al. 2005). Small-caliber vascular prosthesis suitable forgraft conduits for coronary bypass graft-ing, or arteriosclerosis obliterans belowthe knee, for example, have an extremelyhigh failure rate that is attributed tothrombus formationandocclusion. Tissueengineering is a relatively new discipline

249TCM Vol. 17, No. 7, 2007

that offers the potential to create replace-ment structures from autologous cells orother source of stem cells (Campbell andCampbell 2007). The latest and mostexciting developments in this area involvethe use of multipotent stem cells as asource for tissue engineering of vasculargrafts (Campbell and Campbell 2007).

By using stem cells, several labora-tories have produced in vivo, or in vitro,tissue-engineered blood vessels with theuse of moulds or prosthetic or biodegrad-able scaffolds, but each artificial grafthas had significant problems. Recently,conduits have been grown in the perito-neal cavity of the same animal in whichthey will be grafted, ensuring no rejec-tion in the short term of around 2 to3 weeks (Campbell and Campbell 2007).Remodeling occurs after grafting, suchthat the tissue is almost indistinguishablefrom native vessels. This conduit isderived from cells of bone marroworigin, opening new possibilities in vas-cular modeling and remodeling.

Another group reported a novel strat-egy to produce completely biologic tissuesand organs that can display surprisinglyhigh mechanical strength without theneed for any exogenous plastic scaffolds(L'Heureux et al. 1998). Techniques suchas these can produce completely biologicvessels fulfilling the fundamental require-ment for grafting, namely, a high burststrength, positive surgical handling, and afunctional endothelium (L'Heureux et al.1998). These vessels have already beenused successfully as arteriovenous fistulasfor hemodialysis access (L'Heureux et al.2007). The latest and most crucial devel-opments in this area involve the use ofmultipotent stem cells as a cell source fortissue engineering of vascular grafts bothin vivo and in vitro (L'Heureux et al. 2007),which (we believe) will significantlyimprove the outcome of patients withsevere vascular diseases in the future.

� Summary and Prospective

The therapeutic potential of stem andprogenitor cells in vascular disease is avery exciting and important area ofcardiovascular research (Seeger et al.2007). Clearly, despite recent advance-ments in pharmacotherapy and percuta-neous angioplasty techniques, whichhave significantly improved survival andmorbidity, there are still areas, such asvessel restenosis-induced ischemic heart

disease, the treatment of which could beimproved. The major goal to preventpostangioplasty restenosis would be thestimulation of reendothelialization of thecoronary arteries. Stem cells have thepotential to meet the demands of repairand regeneration in diseased vessels byreplacing cells that have been lost ordamaged after balloon angioplasty,thereby restoring the integrity of thevessel and, most importantly, its func-tion. In combination with other technol-ogies, such as tissue engineering, itmay even be possible to direct thesecells to grow in the laboratory into highlyorganized tissues, such as blood vessels,for implantation into patients. Furtherembellishments include the use of ther-apeutic cloning, or somatic cell nuclearreplacement, which may one day makeit possible to generate cells which aregenetic matches with the tissues of thepatient, obviating concerns over immunesystem rejection of the stem cell trans-plant. If successful, stem cell therapyvia therapeutic cloning or other techni-ques would greatly contribute to perso-nalized medicine.

� Acknowledgments

The authors would like to acknowledge allthe collaborators who contributed to thework summarized in the review. This workwas supported by grants from The BritishHeart Foundation and Oak Foundation.

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