Review Article Proangiogenic Features of Mesenchymal Stem...

Review ArticleProangiogenic Features of Mesenchymal Stem Cells andTheir Therapeutic Applications

Hongyan Tao12 Zhibo Han3 Zhong Chao Han3 and Zongjin Li12

1Department of Pathophysiology Nankai University School of Medicine Tianjin 300071 China2The Key Laboratory of Bioactive Materials Ministry of Education Nankai University College of Life Science Tianjin 300071 China3State Key Lab of Experimental Hematology Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical Sciences Tianjin 300020 China

Correspondence should be addressed to Zongjin Li zongjinlinankaieducn

Received 30 June 2015 Revised 4 November 2015 Accepted 29 November 2015

Academic Editor Roberto Gaetani

Copyright copy 2016 Hongyan Tao et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Mesenchymal stem cells (MSCs) have shown their therapeutic potency for treatment of cardiovascular diseases owing to theirlow immunogenicity ease of isolation and expansion and multipotency As multipotent progenitors MSCs have revealed theirability to differentiate into various cell types and could promote endogenous angiogenesis via microenvironmental modulationStudies on cardiovascular diseases have demonstrated that transplantedMSCs could engraft at the injured sites and differentiate intocardiomyocytes and endothelial cells as well Accordingly several clinical trials usingMSCs have been performed and revealed thatMSCsmay improve relevant clinical parameters in patients with vascular diseases To fully comprehend the characteristics ofMSCsunderstanding their intrinsic property and associatedmodulations in tuning their behaviors as well as functions is indispensable forfuture clinical translation of MSC therapy This review will focus on recent progresses on endothelial differentiation and potentialclinical application of MSCs with emphasis on therapeutic angiogenesis for treatment of cardiovascular diseases

1 Introduction

Cardiovascular diseases (CVDs) are one of the major causesof morbidity and mortality worldwide [1] The idea ofpromoting neovascularization and improving perfusion ofischemic tissue via angiogenesis is promising for treatmentof CVDs Since ischemic diseases are primarily causedby endothelial dysfunction the logic behind therapeuticangiogenesis is to promote spontaneous tissue reparationvia endothelial cells (ECs) and growth factor administration[2] However due to the limitation of expanding efficiencyand postnatal cell sources angiogenic therapy with ECs isnot available in most cases [2 3] With their tremendousdifferentiation potency the application of mesenchymal stemcells (MSCs) has been suggested to be a valuable alternativesource for treatment of ischemic diseases Moreover MSCshold great promise for tissue regeneration and revasculariza-tion through stimulating the secretion of various cytokinesresponsible for proangiogenic and antiapoptotic effects [4]

Thus elucidating the paracrine effects and endothelial differ-entiation ofMSCswill not only enhance our understanding ofvascular disease pathogenesis but also improve our ability tofacilitate endothelial differentiation ofMSCs for regenerationpurposes

2 Isolation and Characterization of MSCs

MSCs were first described as stromal cells residing in thebone marrow of rats which have the capacity to transforminto fibroblast-like cells during the processes of tissue repair[5 6] Later in the 1970s Friedenstein et al demonstratedheterogeneous populations of adherent cells within bonemarrow which can replicate as undifferentiated cells and candifferentiate into a variety of mesenchymal cells includingosteoblasts chondrocytes myocytes and adipocytes [7 8]Moreover these kinds of cells are widely distributed and canbe isolated fromadult tissues including bonemarrow adipose

Hindawi Publishing CorporationStem Cells InternationalVolume 2016 Article ID 1314709 11 pageshttpdxdoiorg10115520161314709

2 Stem Cells International

tissue and peripheral blood or neonatal birth-associatedtissues like Whartonrsquos Jelly and placenta [9]

Bone-marrow-derivedMSCs (BM-MSCs) can be isolatedfrom bone marrow aspiration which are among the mostfrequently used types in regenerative studies However theway to get BM-MSCs is accompanied by a risk of infec-tion and is painful for patients which means that findingalternatives is essential in clinical practice Fortunately otherthan bone marrow several kinds of MSCs have been isolatedsuccessfully For example peripheral blood-derived MSCs(PB-MSCs) can be isolated frommononuclear cells of periph-eral blood [10] Adipose-derived MSCs are usually obtainedfrom adipose samples by enzymatic digestion [11] MoreoverWhartonrsquos Jelly of umbilical cord and placenta are consideredto be convenient and readily alternatives to bone marrow[12 13] MSCs derived fromWhartonrsquos Jelly have the weakestexpression of histocompatibility complex class I genes [14]and immune-related genes [15] while they do not expressmajor histocompatibility complex class II genes [14] whichmeans that Whartonrsquos Jelly-derived MSCs are promisingsource for tissue regeneration in clinical application

MSCs are partly differentiated progenitor cells containingmultilineage stem cells and there are no specific and reliablemarkers for defining native MSCs Isolation and purificationof MSCs usually involve density gradient centrifugation orimmunophenotyping [16] The phenotype of MSCs is deter-mined by certain surface markers including CD49a (alpha-1 integrin) CD73 (ecto-51015840-nucleotidase) CD105 (endoglin)MSC antigen-1 CD271 (adapalene) CD29 CD44 CD90 andCD106 (vascular cell adhesionmolecule-1) but lack of CD34CD45 CD14 HLA-DR CD19 and CD79 [17 18] Howeverno specific single marker can be used to identify MSCs fromother kinds of cell types The lack of specific MSCs markershas thwarted the attempts to categorize these kind of stemcells in vivo [19]The specific genotype and proteonomic pro-filesrsquo analysis of multipotential MSCs clones has been carriedout to further elucidate the characterization of MSCs whichare promising to understand themechanisms formaintainingor regulating those cells from different sources [20] CD106 ismainly expressed on blood vessel endothelium which also isan important marker for MSCs [13] Moreover MSCs withhigh expression of transmembrane protein cadherin-2 (N-cadherin) have revealed a higher probability to differentiateinto cardiomyocytes which indicates that MSCs can improveheart function directly [21] The unique subpopulation ofMSCs possessing specific differentiation potency may con-tribute to designed therapeutic strategies

3 Therapeutic Application of MSCs forVascular Regeneration

Despite advances in medical treatment cardiovascular dis-eases (CVDs) are still major causes of adult death Stemcell-based therapy in the treatment of ischemic diseases isa fast-growing field that has been proven effective and safe[22] MSCs can transdifferentiate into all cell lineages ofthree germ layers including blood vessel cells arising frommesodermal tissue which means that it is an attractive cell

Resident CSCs

MSCs

Cardiomyocyte

Cytokines

Endothelium and cardiomyocyte

Tran

sdiffe

rentia

tion

Proli

ferati

on

Paracrine

Activation

Figure 1 MSCs mediated therapy for myocardial infarction (MI)MSCs therapy could enhance heart function by (1) transdifferenti-ation into cardiomyocytes or endothelial cells (ECs) to replace thedamage tissue and promote angiogenesis respectively (2) releasingsoluble autocrineparacrine factors thereby activating endogenousadult cells involved in cells renewalprotection and neovasculariza-tion and (3) stimulating endogenous resident cardiac stem cells(CSCs) proliferation and differentiation by paracrine soluble factors

type for stem cell-based therapy for treatment of CVDs[23] The therapeutic contribution of MSCs to tissue repairincludes direct differentiation into injured cells includingcardiomyocytes smooth muscle cell and ECs presentingcytokines in the microenvironment and stimulating endoge-nous stem cell differentiation (Figure 1) The most necessaryproperty of MSCs for treatment of ischemic diseases is theirdifferentiation potential toward vascular phenotypes whichcan be identified by specific markers or functional assays

31 The Application of MSCs for Ischemia Heart DiseaseTherapy Among the various forms of ischemic diseasesischemic heart disease is a serious disease caused by theimbalance between myocardial oxygen supply and demand[24 25] MSCs transplantation could promote myocardiumrepair by stimulating angiogenesis and MSCs have emergedas a promising cell type for ischemic heart disease therapyboth in small and large animal models [26] For examplethe intravenously injected MSCs derived from rat fetal heartfor treatment ofmyocardial ischemia has achieved significantimprovement in cardiac function [27] The injected cellswere found to express ECs and smooth muscle cells (SMCs)markers suggesting that MSCs can transdifferentiate intoSMCs and ECs This result was also confirmed in largeanimal study In a swine model of chronic ischemic car-diomyopathy the engraftedMSCs were found to differentiateinto cardiomyocytes SMCs and endothelium [28] More-over the efficacy of intramyocardial injection of autologousMSCs has been confirmed in a clinical trial [29] Here wesummarized the use of MSCs in clinical trials in CVDstreatment according to httpsclinicaltrialsgov (Table 1) Anumber of trials are focused on the safety and efficacy ofautologousallogeneic MSCs transplantation The results of

Stem Cells International 3

Table 1 Completed MSC-based randomized clinical trials for ischemic heart disease therapy registered at httpsclinicaltrialsgov

Cell Phase Condition Cell delivery route Basis of trial design Result Reference

AutologousBM-MSCs IIIII AMI Intracoronary

Repairing the damagedmyocardium via paracrine

signaling

Autologous BM-MSCs aresafe and provide modestimprovement in LVEF

[102]

Auto-hMSCs andallo-hMSCs III CILVD Transendocardial

Prevention remodeling ofthe ventricle and reduction

of infarct size

Alloimmune reactions ofallogeneic MSCs injectionare low and improvedfunctions are observed

[103]

AutologousBM-MSCs III Heart attack Intramyocardial

Repair and restore heartfunction by reducing

fibrosis neoangiogenesisand neomyogenesis

Autologous BM-MSCscould reduce scar enhanceregional function andimprove tissue perfusion

[29]

AllogeneicBM-MSCs I MI Intravenous Transdifferentiation of

MSCs into cardiomyocytes

Intravenous allogeneichMSCs are safe in patients

after AMI[104]

Allogeneic BM-MSCs III MI Intravenous

Transdifferentiation ofMSCs into cardiomyocytesand production of new

blood vessels

Intravenous infusion ofallogeneic BM-MSCs is safeand well-tolerated in AMI

patients

[105]

WJ-MSCs II STEMI Intracoronary Transdifferentiation ofMSCs into cardiomyocytes

Intracoronary infusion ofWJ-MSCs is safe and

effective in patients withAMI

[106]

Autologous MSCsand BMCs III LVD Transendocardial Stimulation of endogenous

cardiac stem cells by MSCs

Transendocardial injectionwith MSCs or BMCsappeared to be safe for

patients with ICM and LVD

[107 108]

AD-MSCs II CMI Not special Angiogenesis mdash mdash

AutologousBM-MSC III CHF Intramyocardial

Development of newmyocardium and blood

vessels

Intramyocardial injectionsof autologous culture

expanded MSCs were safeand improved myocardial

function

[109 110]

Notes BM-MSCs bone-marrow-derived human MSCs WJ-MSCs umbilical Whartonrsquos Jelly-derived mesenchymal stem cell AD-MSCs adipose-derivedmesenchymal stem cells auto-hMSCs autologous human mesenchymal stem cells allo-hMSCs allogeneic human mesenchymal stem cells BMCs bonemarrowmononuclear cells AMI acutemyocardial infarction LVEF left ventricular ejection fraction STEMI ST elevationmyocardial Infarction ICM chronicischemic cardiomyopathy CMI chronic myocardial ischemia IHF ischemic heart failure CHF congestive heart failure and CILVD chronic ischemic leftventricular dysfunction

these trials have confirmed that MSCs injection is safe andhas the capability to improve cardiac function Despite thesepositive results additional clinical trials are still encouragedto determinewhether stem cell-based therapy could serve as anovel alternative tool for treatment of ischemic heart disease

Tissue injury andor inflammation caused by ischemiacan enhance the efficacy ofMSCs homing to the injury tissuewhichmay provide an avenue for clinical translation ofMSCsin the future as a cellular tool for CVDs therapeutics [30]MSCs expressing various surface receptors could respond tothe migratory signals released by sites of injury Meanwhilemany studies to modify andor enhance expression of thesesurface markers have been explored [31] Therefore opti-mized culture conditions biomaterials and gene transfectioncan be used to enhance migration ability of MSCs homing tothe sites of injury Although MSCs are the most promisingsources of regeneration medicine their poor cell viabilityafter transplantation imposes restrictions on their clinical

applications Therefore another aspect of research interestis improving cell survival rate after transplantation MSCsgenetically transduced with Akt1 (protein kinase B) canimprove MSCs survival while infarcted myocardium repa-ration was enhanced [32] The other approaches to enhanceMSCs survival in ischemic tissue include hypoxic precon-ditioning genetic modification and angiogenin expression[33 34] and these methods highlight the utility of gene-engineered cells and preconditioning cells

The exact pathway of acute donor cell death followingtransplantation is still unknown but lack of matrix supportis one of major causes [2] Engineered microenvironmentswith extracellular matrix and growth factors mimickingthe establishment of cell niche in vivo have achieved greatimprovement in controlling stem cell fate [35ndash37] Further-more the use of different polymers can help delivering drugsviruses plasmids and cytokines [38] Transplantation of theconstruct of tissue-engineered cardiac patch with BM-MSCs


for immunocompetent rats after myocardial infarction hasresulted in increased fractional shortening augmented ante-rior wall thickness and reduced left ventricle interior diam-eter at systole [39] A similar study of a three-dimensionalscaffolds transplantation that contain more than a few layersof BM-MSCs also led to heart function improvement andformation of MSC-derived neovasculatures [40]

32 The Application of MSCs for Treatment of PeripheralArtery Disease (PAD) Peripheral artery disease (PAD) is aserious disease usually caused by atherosclerotic occlusionwhich can lead to critical limb ischemia tissue injuries andeventual limb loss [41 42]The patients with PAD have a verypoor long-term prognosis only 30 of patients can live for15 years after being diagnosed with this disease [43] Criticallimb ischemia is themost serious complication of PADwhichcan cause pain on walking or even at rest and nonhealingulcers Although patients with limb ischemia are treated witha combination of methods such as statins antiplatelet drugsand angioplasty these treatments are occasionally insufficientto recover sufficient arterial blood flow to maintain tissueviability [44] Therefore it is urgent need to develop noveltreatment approaches for revascularization of ischemic limbsto repair the injured tissues

Currently one of themost fundamentalmethods for PADtreatment is therapeutic angiogenesis which aims to promoteneovascularization and restore blood flow to ischemic limbsby forming new blood vessels from preexisting ones [45]Theevidences that MSCs transplantation could achieve this pur-pose have been confirmed by small and large animal studies[46 47] And the use of MSCs has already started in the firstclinical trials and the safetyefficacy of MSCs was confirmed[48 49] In a double-blind controlled randomized trialin patients with critical limb ischemia caused by diabetes[50] ulcer size pain-free walking time and percutaneoustissue oxygen pressure were significantly improved in MSCstreated group and the production of VEGF and FGF-2was significantly higher in the MSCs group compared togroups of other kinds of cells from bone marrow Althoughfurther basic investigations should be carried out this clinicaltrial proved that MSCs hold great promise for vascularregeneration

Both animal studies and clinical trials established theevidence that therapeutic angiogenesis with MSCs can beregarded as an effective approach for treatment of PAD Thetherapy potential is based on the transplantation of MSCswhich could enhance neovascularization thereby rescuingthe ischemic tissues from degeneration However before weapply this approach to clinical the therapeutic potential andscientific support of MSCs transdifferentiation need to befurther investigated [51] Future studies will be undoubtedlyconfident that all these basic studies and clinical trials oftherapeutic neovascularization will improve outcomes inPAD

33 MSCs for Vascular Bioengineering Vascular grafts areincreasingly needed in the clinic for coronary disease andhemodialysis [52 53] Unfortunately the acute thrombosis

and subsequent occlusion often lead to the failure of thetransplanted synthetic acellular vascular grafts Commonmodels of living vascular grafts have been developed to somedifferent types like matrix or cells alone or hybrid vasculargrafts combined with cells matrix and soluble factors [54]Because of their superior proliferation capacity and lowerimmunogenicity as an excellent cellular candidate for off-the-shelf therapy MSCs represent a suitable alternative stem cellsource [55] MSCs have mainly three critical functions (1)homing to the site where tissues are damaged (2) secretingcytokines or chemokines to facilitate the migration of hostcells and (3) transdifferentiating into functional ECs [56]

In clinical application tissue-engineered vascular grafts(TEVGs) are supposed to have mechanically durable struc-ture and antithrombogenesis ability Most approaches ofTEVG fabrication rely on the forms of scaffold to providemechanical integrity upon implantation to the arterial circu-lation In vivo transplantation of acellular conduits or MSC-seeded vascular grafts as interpositional grafts suggestedthat MSCs could block the inflammatory responses inducedby nanofibrous scaffolds [57] The combined application ofpolymer grafts and MSCs for developing vascular conduitsconfers TEVGs with mechanical strength good tissue com-patibility and ability of remodeling

Genetic modification of MSCs to mimic the functionof ECs has been reported Rat BM-MSCs were transducedwith eNOS and can release nitric oxide (NO) subsequentlyNO is normally released by ECs to offer feasible effectsof angiogenesis on the native coronary arteries as wellas improve self-patency and prevent thrombogenesis [58]Adipose-derived cells with transfection of eNOS gene couldproduce significant amounts of NO which indicate thepossibility of NO production of an engineered vascular [59]This hybrid vascular prosthesis is expected to provide atherapeutic advantage by extended production of NO fromthe inner surfaces

In addition to cells alone to investigate spatial orientationofMSCs related to the engineered vascularMSCs and humanumbilical vein endothelial cells (HUVECs) were transducedrespectively with retrovirus to express DsRed and EGFP[60] They found that undifferentiated MSCs combined withHUVECs seeded on a graft are able to grow in vivo andfunction as pericytes wrapping around the endothelial tubes(Figure 2) Moreover the angiogenic applications of MSCsare not only based on their ability to differentiate into ECs butalso on their differentiation ability toward SMCs phenotypeIn response to TGF-120573 MSCs have been revealed to transd-ifferentiate into SMCs by direct contact with vascular ECsmechanical stress and prostaglandin F

2120572(PGF2120572) [61 62]

The intramuscular injection of TGF-1205731-induced human adi-pose tissue-derived MSCs could improve neovascularizationand blood perfusion significantly [63] These results indicatethe important role of MSCs in therapeutic angiogenesis

4 Paracrine Mechanisms behind MSCsAngiogenic Potential

Despite the acute donor cell death after transplantation bothanimal and clinical studies have demonstrated beneficial


(a) (b)

(c) (d)

(e) (f)

(g)

Figure 2 Intravitalmicroscope analysis revealed thatMSCs behaved like pericytes wrapping around the vessel in a tissue-engineered vascularmodel With multiphoton laser scanningmicroscopy (MPLSM) images were taken at different time points Lumen formation and blood flowin hMSCs (EGFP+) derived cells were not able to detect (a) On the contrary implant HUVECs (DsRed+) and hMSCs (EGFP+) in micehMSCs (EGFP+) could be found elongate into thin slit structures and coalesced around the HUVEC-derived vessels (b)ndash(f) Over time thenumber of interstitial hMSCs (EGFP+) was decreased and most of them were associated with blood vessels by day 83 (g) Reprinted withpermission from [60]


effects of the treatment which indicate that stem cells perhapsact through paracrine pathways [3] Cell-free conditionedmedium from MSCs can induce angiogenesis through acti-vation of VEGF-A expression and secretion in ECs [64]Another experiments also revealed that conditionedmediumfrom bone marrow or adipose tissue also has got positiveeffect on angiogenesis [65ndash67] profiting in which fromMSCsrsquoangiogenic paracrine secretion of HGF bFGF IGF-1 andVEGF [68] Besides exosomes released byMSCsmay serve asan essential mediator of angiogenesis by transferring geneticmaterials and angiogenic molecules Those results indicatethat the paracrine cytokines and exosomes of MSCs havea complex composition rather than single molecule all ofwhich could participate in regenerative processes

41 Growth Factor Production MSCs could be recruited andmobilized to the sites of inflammation as well as injury wherethey can incorporate into the ischemic tissuersquos microenviron-ment After cells transplant the angiogenic paracrine effectsof MSCs could improve tissue functions in the ischemiclimb [69] MSCs can potentiate angiogenesis via directdifferentiation cell contact interaction or paracrine effects[70] Angiogenic factors produced by MSCs include bFGFVEGF TGF-120573 PDGF angiopoietin-1 placental growth factor(PGF) IL-6 and monocyte chemotactic protein-1 (MCP-1)which facilitate tissue regeneration

MSCs could stimulate angiogenesis in vitro and in vivothrough secretedVEGFMCP-1 and IL-6 into their conditionmedium and these effects can be significantly inhibitedby pretreatment with neutralizing antibodies against VEGFMCP-1 and IL-6 [71] IL-6 is an MSC-secreted cell fac-tor displaying proangiogenic progrowth and prosurvivalactivities [72] which has potent proangiogenic and anti-apoptotic activity MCP-1 can be detected among MSC-secreted cytokines and is a critical chemoattractant forangiogenesis [67] Last but not least the most importantproangiogenic factor VEGF has been shown possible to beexpressed by MSCs as well as promote MSCs differentiation[73] Meanwhile VEGF has been revealed to regulate ECsmigrations and differentiation and promote recruitment ofECs for angiogenesis and endothelialization in injured tissue[44] The receptors of VEGF include VEGFR2 (KDRFlk1)and tyrosine kinase receptors VEGFR1 (Flt1) [74] VEGFR2induces activation of various signaling pathways includingthe activation of mitogen-activated protein kinase (MAPK)phosphoinositide-3-kinase and Akt (PI3KAKT) Src andRac pathways VEGFR2 is the main receptor involved in cellsignaling for its strong tyrosine kinase activity [75]

MSCs are able to secrete a composite of angiogenic factorslike HGF and stromal-cell-derived factor-1 (SDF-1) whichcan promote local angiogenesis [76] SDF-1 is an inducibleand constitutively expressed chemokine that can regulatemultiple physiological processes such as stimulating ECsproliferation and capillary tube formation [77] HGF exertsits angiogenic activity through tyrosine phosphorylation of itsspecific receptor c-Met which can be found in ECs and SMCs[78] The therapeutic efficacy of HGF has been investigated

in a clinical trial [79] and shown to possess multiple effects inpatients with critical limb ischemia

MSCs have both autocrine and paracrine activities whichare involved in cell survival organ function and tissueangiogenesis [67 80] Growth factors mentioned above likeVEGF MCP-1 HGF TGF-120573 and IL-6 are potent angiogenicfactors which could improve angiogenesis and restoration ofPAD and CVDs [81] With these angiogenic factors MSCs-based treatment after tissue injured could increase microvas-cular density and preserve organ function through increasingtissue perfusion [81] In accordance with these observationsMSCs with various paracrine angiogenic factors are able toenhance in vivo angiogenesis and local blood flow recoveryin the ischemic tissue

42 Exosomes and MicroRNA Production The angiogeniccytokines are one of the crucial factors of angiogenesis whichcan support cell growth proliferation and communicationHowever multiple studies show that the communicationbetween MSCs and other cells is not only through cytokinesbut also through exerting their function via exosomes Exo-somes are small particles dynamically composed by lipidsproteins cytoskeletal elements molecular chaperones andsignaling molecules that can also convey biological materialsto surrounding cells [82 83] More recently evidences thatexosomes contain genetic materials including mRNAs andmicroRNAs have emerged [84] and these exosomes can befunctional for recipient cells Results suggest that exosomesmay serve as an essential mediator of angiogenesis by trans-ferring genetic materials and angiogenic molecules

Exosomes with miRNAs can be secreted by a varietyof cell types such as cardiocytes vascular cells and MSCsin culture [85] and the altered expression of miRNAs hasbeen correlatedwith CVDsThe discovery ofmiRNAvesicle-mediated communication between endothelial cells and car-diovascular cells was confirmed recently [86 87] MoreovermiRNAs have been detected in the supernatant of humanMSCs that may be associated with exosomes [88]These exo-somes were injected into a rat model of ischemiareperfusionand revealed cardioprotective effect [89]The result indicatedthat exosomes secreted by MSCs might possess therapeuticpotential Although significant progresses have been made inCVDs therapy further investigations are needed to explorethe therapeutic potency of MSCs-derived exosomes Futureclinical use of exosomes in diagnosis monitoring diseaseprogress treatment and monitoring treatment efficacy ispromising

5 Endothelial Differentiation of MSCs

Human MSCs have been confirmed to be pluripotent pro-genitors that can replicate as multiple types of cells includinglineages with phenotypic and functional features of ECs [90]Further in vivo research also showed that engrafted MSCswere positive for vWF suggesting their transdifferentiationinto ECs [91] Since MSCs can differentiate into ECs thismeans that MSCs have the ability to participate in postnatalangiogenesis and form vasculature in vivo [92] Those results


Cytokines

Proliferationmigration

ECs endothelial cells

Transdifferentiation

Paracrine effects

MSCs mesenchymal stem cells

Angiogenesis

Endogenous ECs

Figure 3 Angiogenic potency ofMSCsMSCs could promote angiogenesis either by paracrine effects or by transdifferentiationThe secretionof cytokines could enhance the proliferation and migration of endogenous endothelial cells Moreover MSCs may transdifferentiate intolineage with functional and phenotypic features of ECs and participate in angiogenesis directly

confirmed that MSCs could be a viable source for the de novogeneration of ECs for therapeutic angiogenesis application(Figure 3)

IsolatedMSCswere negative for typical endothelialmark-ers like eNOS VE-cadherin vWF and pericyte markers(NG2 and platelet-derived growth factor receptor 120573) [93]and those markers can be used to establish the identityof endothelial differentiation of MSCs Moreover MSCsisolated from human Whartonrsquos Jelly were negative for typ-ical endothelial markers and eNOS protein expression wasincreased significantly after endothelial transdifferentiation[18] which has been proved in MSCs from other sourcesas well Another research interest lies in the impact of NOsignaling during the process of MSCs transdifferentiationinto ECs [94] It has been revealed that NO signaling is anessential regulator of vasculogenesis in MSCsThese findingsoffer exciting insights for MSCs-based angiogenic therapy

VEGF is amajor factor in the process of endothelial differ-entiation which can induce the endothelial differentiation ofMSCs [65 95 96] A study implied thatVEGF induces humanBM-MSCs differentiation into ECs by RhoROCK signalingpathway Blocking RhoROCK pathway could suppress theupregulation of tube formation migration and proliferationof ECs [97 98] Moreover PDGF could induce endothelialdifferentiation ofMSCs [99] whereas TGF-120573 plays an impor-tant role in cell differentiation and vascular remodeling [100]It has been revealed that TGF-120573 could increase the expressionof smooth muscle 120573-actin while decreasing the expressionof gelsolin according to proteomic profiling analysis [101]which will lead to more focused and in-depth research on theinfluences of TGF-120573 on endothelial differentiation of MSCs

6 Conclusions

Over the last decadeMSCs have been proved for engineeringvascular conduits or treatment of ischemic diseases MSCshave drawn considerable attention because of their poten-tial to differentiate into cardiovascular lineages and theirpromising therapeutic prospective and beneficial properties

for CVDs MSCs can be applied to a variety of clinicalscenarios not only through cell-cell interactions but alsothroughmultiple paracrine factorsTherefore understandingthe intrinsic properties and associatedmodulations in tuningMSCsrsquo behaviors as well as functions is indispensable forfuture therapeutic applications of MSCs Clearly elucidatingthe mechanisms of endothelial differentiation and therapeu-tic angiogenesis of MSCs will offer more simple definitiveand effective approaches for treatment of ischemic CVDs

Conflict of Interests

The authors declare no potential conflict of interests

Authorsrsquo Contribution

All authors (Hongyan Tao ZhiboHan ZhongChaoHan andZongjin Li) have made substantive intellectual contributionsto this study according to ICMJE guidelines All of them havebeen qualified as authors All authors read and approved thefinal paper

Acknowledgments

This work was partially supported by grants from theNational Natural Science Foundation of China (8137162031470951 and 81320108014) the National Basic Research Pro-gram of China (2011CB964903) and Program for ChangjiangScholars and Innovative Research Team in University(IRT13023)

References

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[2] M M Daadi Z Li A Arac et al ldquoMolecular and magneticresonance imaging of human embryonic stem cell-derived


neural stem cell grafts in ischemic rat brainrdquoMolecularTherapyvol 17 no 7 pp 1282ndash1291 2009

[3] Z Li K D Wilson B Smith et al ldquoFunctional and transcrip-tional characterization of human embryonic stem cell-derivedendothelial cells for treatment of myocardial infarctionrdquo PLoSONE vol 4 no 12 Article ID e8443 2009

[4] L Zimmerlin T S Park E T Zambidis V S Donnenbergand A D Donnenberg ldquoMesenchymal stem cell secretome andregenerative therapy after cancerrdquo Biochimie vol 95 no 12 pp2235ndash2245 2013

[5] R Ross N B Everett and R Tyler ldquoWound healing andcollagen formation VI The origin of the wound fibroblaststudied in parabiosisrdquo The Journal of Cell Biology vol 44 no3 pp 645ndash654 1970

[6] N L Petrakis M Davis and S P Lucia ldquoThe in vivo differ-entiation of human leukocytes into histiocytes fibroblasts andfat cells in subcutaneous diffusion chambersrdquo Blood vol 17 pp109ndash118 1961

[7] A J Friedenstein U F Gorskaja and N N Kulagina ldquoFibrob-last precursors in normal and irradiated mouse hematopoieticorgansrdquo Experimental Hematology vol 4 no 5 pp 267ndash2741976

[8] D Cook and P Genever ldquoRegulation of mesenchymal stemcell differentiationrdquo Advances in Experimental Medicine andBiology vol 786 pp 213ndash229 2013

[9] R Hass C Kasper S Bohm and R Jacobs ldquoDifferent popu-lations and sources of human mesenchymal stem cells (MSC)a comparison of adult and neonatal tissue-derived MSCrdquo CellCommunication and Signaling vol 9 article 12 2011

[10] I Kassis L Zangi R Rivkin et al ldquoIsolation of mesenchymalstem cells from G-CSF-mobilized human peripheral bloodusing fibrin microbeadsrdquo Bone Marrow Transplantation vol 37no 10 pp 967ndash976 2006

[11] J W Kuhbier B Weyand C Radtke P M Vogt C Kasperand K Reimers ldquoIsolation characterization differentiationand application of adipose-derived stem cellsrdquo in BioreactorSystems for Tissue Engineering II vol 123 of Advances inBiochemical EngineeringBiotechnology pp 55ndash105 SpringerBerlin Germany 2010

[12] W Gong Z Han H Zhao et al ldquoBanking human umbilicalcord-derived mesenchymal stromal cells for clinical userdquo CellTransplantation vol 21 no 1 pp 207ndash216 2012

[13] Z X Yang Z-B Han Y R Ji et al ldquoCD106 identifies a subpop-ulation of mesenchymal stem cells with unique immunomod-ulatory propertiesrdquo PLoS ONE vol 8 no 3 Article ID e593542013

[14] R Sarugaser L Hanoun A Keating W L Stanford and JE Davies ldquoHuman mesenchymal stem cells self-renew anddifferentiate according to a deterministic hierarchyrdquo PLoS ONEvol 4 no 8 Article ID e6498 2009

[15] X Li J Bai X Ji R Li Y Xuan and Y Wang ldquoComprehensivecharacterization of four different populations of human mes-enchymal stem cells as regards their immune properties prolif-eration and differentiationrdquo International Journal of MolecularMedicine vol 34 no 3 pp 695ndash704 2014

[16] N F Huang and S Li ldquoMesenchymal stem cells for vascularregenerationrdquo Regenerative Medicine vol 3 no 6 pp 877ndash8922008

[17] A R Williams and J M Hare ldquoMesenchymal stem cells biol-ogy pathophysiology translational findings and therapeuticimplications for cardiac diseaserdquo Circulation Research vol 109no 8 pp 923ndash940 2011

[18] V Aguilera L Briceno H Contreras et al ldquoEndothelium transdifferentiated fromWhartonrsquos jelly mesenchymal cells promotetissue regeneration potential role of soluble pro-angiogenicfactorsrdquo PLoS ONE vol 9 no 11 Article ID e111025 2014

[19] F-J Lv R S Tuan K M C Cheung and V Y L LeungldquoConcise review the surface markers and identity of humanmesenchymal stem cellsrdquo STEMCELLS vol 32 no 6 pp 1408ndash1419 2014

[20] S Law and S Chaudhuri ldquoMesenchymal stem cell and regener-ative medicine regeneration versus immunomodulatory chal-lengesrdquo American Journal of Stem Cells vol 2 no 1 pp 22ndash382013

[21] H Ishimine N Yamakawa M Sasao et al ldquoN-Cadherin is aprospective cell surface marker of human mesenchymal stemcells that have high ability for cardiomyocyte differentiationrdquoBiochemical andBiophysical ResearchCommunications vol 438no 4 pp 753ndash759 2013

[22] M Das I B Sundell and P S Koka ldquoAdult mesenchymal stemcells and their potency in the cell-based therapyrdquo Journal of StemCells vol 8 no 1 pp 1ndash16 2013

[23] L Chen Y Xu J Zhao et al ldquoConditioned mediumfrom hypoxic bone marrow-derived mesenchymal stem cellsenhances wound healing in micerdquo PLoS ONE vol 9 no 4Article ID e96161 2014

[24] Q Zhao and Z Li ldquoAngiogenesisrdquo BioMed Research Interna-tional vol 2015 Article ID 135861 2 pages 2015

[25] L Wang W Su W Du et al ldquoGene and MicroRNA profiling ofhuman induced pluripotent stem cell-derived endothelial cellsrdquoStem Cell Reviews and Reports vol 11 pp 219ndash227 2015

[26] F Dong J Harvey A Finan K Weber U Agarwal and MS Penn ldquoMyocardial CXCR4 expression is required for mes-enchymal stem cell mediated repair following acute myocardialinfarctionrdquo Circulation vol 126 no 3 pp 314ndash324 2012

[27] V N S Garikipati S Jadhav L Pal P Prakash M Dikshitand S Nityanand ldquoMesenchymal stem cells from fetal heartattenuate myocardial injury after infarction an in vivo serialpinhole gated SPECT-CT study in ratsrdquo PLoS ONE vol 9 no6 Article ID e100982 2014

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[29] V Karantalis D L DiFede G Gerstenblith et al ldquoAutologousmesenchymal stem cells produce concordant improvements inregional function tissue perfusion and fibrotic burden whenadministered to patients undergoing coronary artery bypassgrafting the Prospective Randomized Study of MesenchymalStem Cell Therapy in Patients Undergoing Cardiac Surgery(PROMETHEUS) trialrdquo Circulation Research vol 114 no 8 pp1302ndash1310 2014

[30] F Li Q Huang J Chen et al ldquoApoptotic cells activate thelsquophoenix risingrsquo pathway to promote wound healing and tissueregenerationrdquo Science Signaling vol 3 no 110 article ra13 2010

[31] M W Maijenburg C Gilissen S M Melief et al ldquoNuclearreceptors Nur77 andNurr1 modulate mesenchymal stromal cellmigrationrdquo Stem Cells and Development vol 21 no 2 pp 228ndash238 2012

[32] A A Mangi N Noiseux D Kong et al ldquoMesenchymalstem cells modified with Akt prevent remodeling and restoreperformance of infarcted heartsrdquo Nature Medicine vol 9 no 9pp 1195ndash1201 2003


[33] D Simpson H Liu T-H M Fan R Nerem and S C DudleyJr ldquoA tissue engineering approach to progenitor cell deliveryresults in significant cell engraftment and improved myocardialremodelingrdquo Stem Cells vol 25 no 9 pp 2350ndash2357 2007

[34] X-H Liu C-G Bai Z-Y Xu et al ldquoTherapeutic potentialof angiogenin modified mesenchymal stem cells angiogeninimproves mesenchymal stem cells survival under hypoxia andenhances vasculogenesis inmyocardial infarctionrdquoMicrovascu-lar Research vol 76 no 1 pp 23ndash30 2008

[35] X Yao Y Liu J Gao et al ldquoNitric oxide releasing hydrogelenhances the therapeutic efficacy of mesenchymal stem cells formyocardial infarctionrdquo Biomaterials vol 60 pp 130ndash140 2015

[36] N He Y Xu W Du et al ldquoExtracellular matrix can recoverthe downregulation of adhesionmolecules after cell detachmentand enhance endothelial cell engraftmentrdquo Scientific Reportsvol 5 Article ID 10902 2015

[37] W Du H Tao S Zhao Z He and Z Li ldquoTranslationalapplications ofmolecular imaging in cardiovascular disease andstem cell therapyrdquo Biochimie vol 116 pp 43ndash51 2015

[38] D M Nelson R Hashizume T Yoshizumi A K Blakney ZMa andW RWagner ldquoIntramyocardial injection of a synthetichydrogel with delivery of bFGF and IGF1 in a rat model ofischemic cardiomyopathyrdquo Biomacromolecules vol 15 no 1 pp1ndash11 2014

[39] D L Simpson and S C Dudley Jr ldquoModulation of humanmesenchymal stem cell function in a three-dimensional matrixpromotes attenuation of adverse remodelling after myocardialinfarctionrdquo Journal of Tissue Engineering and RegenerativeMedicine vol 7 no 3 pp 192ndash202 2013

[40] H-J Wei C-H Chen W-Y Lee et al ldquoBioengineered cardiacpatch constructed from multilayered mesenchymal stem cellsfor myocardial repairrdquo Biomaterials vol 29 no 26 pp 3547ndash3556 2008

[41] Z Raval and D W Losordo ldquoCell therapy of peripheralarterial disease from experimental findings to clinical trialsrdquoCirculation Research vol 112 no 9 pp 1288ndash1302 2013

[42] H Orbay Y Zhang H Hong et al ldquoPositron emission tomog-raphy imaging of angiogenesis in a murine hindlimb ischemiamodel with 64Cu-labeled TRC105rdquo Molecular Pharmaceuticsvol 10 no 7 pp 2749ndash2756 2013

[43] Y Zhang R Zhang Y Li G He D Zhang and F ZhangldquoSimvastatin augments the efficacy of therapeutic angiogenesisinduced by bone marrow-derived mesenchymal stem cells ina murine model of hindlimb ischemiardquo Molecular BiologyReports vol 39 no 1 pp 285ndash293 2012

[44] M Shimamura H Nakagami H Koriyama and R Mor-ishita ldquoGene therapy and cell-based therapies for therapeuticangiogenesis in peripheral artery diseaserdquo BioMed ResearchInternational vol 2013 Article ID 186215 8 pages 2013

[45] J D Ransohoff and J C Wu ldquoImaging stem cell therapy forthe treatment of peripheral arterial diseaserdquo Current VascularPharmacology vol 10 no 3 pp 361ndash373 2012

[46] J Qin K Li C Peng et al ldquoMRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemiardquo Biomaterialsvol 34 no 21 pp 4914ndash4925 2013

[47] A Bronckaers P Hilkens W Martens et al ldquoMesenchy-mal stemstromal cells as a pharmacological and therapeuticapproach to accelerate angiogenesisrdquo Pharmacology and Ther-apeutics vol 143 no 2 pp 181ndash196 2014

[48] H Suzuki and Y Iso ldquoClinical application of vascular regen-erative therapy for peripheral artery diseaserdquo BioMed ResearchInternational vol 2013 Article ID 179730 6 pages 2013

[49] R J Powell A J Comerota S A Berceli et al ldquoInterim analysisresults from the RESTORE-CLI a randomized double-blindmulticenter phase II trial comparing expanded autologous bonemarrow-derived tissue repair cells and placebo in patients withcritical limb ischemiardquo Journal of Vascular Surgery vol 54 no4 pp 1032ndash1041 2011

[50] D Lu B Chen Z Liang et al ldquoComparison of bone marrowmesenchymal stem cells with bone marrow-derived mononu-clear cells for treatment of diabetic critical limb ischemiaand foot ulcer a double-blind randomized controlled trialrdquoDiabetes Research and Clinical Practice vol 92 no 1 pp 26ndash362011

[51] A Grochot-Przeczek J Dulak and A Jozkowicz ldquoTherapeuticangiogenesis for revascularization in peripheral artery diseaserdquoGene vol 525 no 2 pp 220ndash228 2013

[52] Z Wang Y Cui J Wang et al ldquoThe effect of thick fibersand large pores of electrospun poly(120576-caprolactone) vasculargrafts on macrophage polarization and arterial regenerationrdquoBiomaterials vol 35 no 22 pp 5700ndash5710 2014

[53] K Wang X Chen Y Pan et al ldquoEnhanced vascularizationin hybrid PCLgelatin fibrous scaffolds with sustained releaseof VEGFrdquo BioMed Research International vol 2015 Article ID865076 10 pages 2015

[54] N LrsquoHeureux S Paquet R Labbe L Germain and F AAuger ldquoA completely biological tissue-engineered human bloodvesselrdquoThe FASEB Journal vol 12 no 1 pp 47ndash56 1998

[55] Z-Y Zhang S-H Teoh J H P Hui N M Fisk M Choolaniand J K Y Chan ldquoThe potential of human fetal mesenchymalstem cells for off-the-shelf bone tissue engineering applicationrdquoBiomaterials vol 33 no 9 pp 2656ndash2672 2012

[56] J T Krawiec J S Weinbaum C M St Croix et al ldquoAcautionary tale for autologous vascular tissue engineeringimpact of human demographics on the ability of adipose-derivedmesenchymal stem cells to recruit and differentiate intosmooth muscle cellsrdquo Tissue Engineering Part A vol 21 no 3-4pp 426ndash437 2015

[57] C K Hashi Y Zhu G-Y Yang et al ldquoAntithrombogenic prop-erty of bone marrow mesenchymal stem cells in nanofibrousvascular graftsrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 104 no 29 pp 11915ndash119202007

[58] S Kanki-HorimotoHHorimoto SMieno et al ldquoImplantationof mesenchymal stem cells overexpressing endothelial nitricoxide synthase improves right ventricular impairments causedby pulmonary hypertensionrdquo Circulation vol 114 no 1 pp I-181ndashI-185 2006

[59] S Mcilhenny P Zhang T Tulenko et al ldquoeNOS transfectionof adipose-derived stem cells yields bioactive nitric oxide pro-duction and improved results in vascular tissue engineeringrdquoJournal of Tissue Engineering and Regenerative Medicine vol 9no 11 pp 1277ndash1285 2015

[60] P Au J Tam D Fukumura and R K Jain ldquoBone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculaturerdquo Blood vol 111 no 9 pp 4551ndash4558 2008

[61] F F Cunha LMartins P KMMartin R S Stilhano and SWHan ldquoA comparison of the reparative and angiogenic propertiesof mesenchymal stem cells derived from the bone marrow ofBALBc and C57BL6 mice in a model of limb ischemiardquo StemCell Research ampTherapy vol 4 no 4 article 86 2013

[62] M J Lee M Y Kim S C Heo et al ldquoMacrophages regulatesmooth muscle differentiation of mesenchymal stem cells via a


prostaglandin F2120572-mediated paracrinemechanismrdquoArterioscle-

rosis Thrombosis and Vascular Biology vol 32 no 11 pp 2733ndash2740 2012

[63] W S Park S C Heo E S Jeon et al ldquoFunctional expression ofsmoothmuscle-specific ion channels in TGF-120573

1-treated human

adipose-derived mesenchymal stem cellsrdquo American Journalof PhysiologymdashCell Physiology vol 305 no 4 pp C377ndashC3912013

[64] L Bussche and G R Van de Walle ldquoPeripheral blood-derivedmesenchymal stromal cells promote angiogenesis via paracrinestimulation of vascular endothelial growth factor secretion inthe equine modelrdquo Stem Cells Translational Medicine vol 3 no12 pp 1514ndash1525 2014

[65] Y Xu L Liu L Zhang et al ldquoEfficient commitment tofunctional CD34+ progenitor cells from human bone mar-row mesenchymal stem-cell-derived induced pluripotent stemcellsrdquo PLoS ONE vol 7 no 4 Article ID e34321 2012

[66] S H Bhang S Lee J-Y Shin T-J Lee H-K Jang andB-S Kim ldquoEfficacious and clinically relevant conditionedmedium of human adipose-derived stem cells for therapeuticangiogenesisrdquo Molecular Therapy vol 22 no 4 pp 862ndash8722014

[67] R A Boomsma and D L Geenen ldquoMesenchymal stem cellssecrete multiple cytokines that promote angiogenesis and havecontrasting effects on chemotaxis and apoptosisrdquo PloSONE vol7 no 4 Article ID e35685 2012

[68] N A Sopko B A Turturice M E Becker et al ldquoBone marrowsupport of the heart in pressure overload is lost with agingrdquoPLoS ONE vol 5 no 12 Article ID e15187 2010

[69] S Schlosser C Dennler R Schweizer et al ldquoParacrine effectsof mesenchymal stem cells enhance vascular regeneration inischemic murine skinrdquo Microvascular Research vol 83 no 3pp 267ndash275 2012

[70] S M Watt F Gullo M van der Garde et al ldquoThe angiogenicproperties of mesenchymal stemstromal cells and their ther-apeutic potentialrdquo British Medical Bulletin vol 108 no 1 pp25ndash53 2013

[71] H M Kwon S-M Hur K-Y Park et al ldquoMultiple paracrinefactors secreted by mesenchymal stem cells contribute toangiogenesisrdquo Vascular Pharmacology vol 63 no 1 pp 19ndash282014

[72] S Botto D N Streblow V DeFilippis et al ldquoIL-6 in humancytomegalovirus secretome promotes angiogenesis and survivalof endothelial cells through the stimulation of survivinrdquo Bloodvol 117 no 1 pp 352ndash361 2011

[73] B M Beckermann G Kallifatidis A Groth et al ldquoVEGFexpression by mesenchymal stem cells contributes to angiogen-esis in pancreatic carcinomardquo British Journal of Cancer vol 99no 4 pp 622ndash631 2008

[74] A D Berendsen and B R Olsen ldquoHow vascular endothelialgrowth factor-A (VEGF) regulates differentiation of mesenchy-mal stem cellsrdquo The Journal of Histochemistry and Cytochem-istry vol 62 no 2 pp 103ndash108 2014

[75] S Koch S Tugues X Li L Gualandi and L Claesson-WelshldquoSignal transduction by vascular endothelial growth factorreceptorsrdquoThe Biochemical Journal vol 437 no 2 pp 169ndash1832011

[76] M Pasquet M Golzio E Mery et al ldquoHospicells (ascites-derived stromal cells) promote tumorigenicity and angiogene-sisrdquo International Journal of Cancer vol 126 no 9 pp 2090ndash2101 2010

[77] M Zhou Z Liu C Liu et al ldquoTissue engineering of small-diameter vascular grafts by endothelial progenitor cells seedingheparin-coated decellularized scaffoldsrdquo Journal of BiomedicalMaterials Research Part B Applied Biomaterials vol 100 no 1pp 111ndash120 2012

[78] T Kaga H Kawano M Sakaguchi T Nakazawa Y Taniyamaand R Morishita ldquoHepatocyte growth factor stimulated angio-genesis without inflammation differential actions betweenhepatocyte growth factor vascular endothelial growth factorand basic fibroblast growth factorrdquo Vascular Pharmacology vol57 no 1 pp 3ndash9 2012

[79] H Shigematsu K Yasuda T Iwai et al ldquoRandomized double-blind placebo-controlled clinical trial of hepatocyte growthfactor plasmid for critical limb ischemiardquo GeneTherapy vol 17no 9 pp 1152ndash1161 2010

[80] K-S Park Y-S Kim J-H Kim et al ldquoTrophic moleculesderived from humanmesenchymal stem cells enhance survivalfunction and angiogenesis of isolated islets after transplanta-tionrdquo Transplantation vol 89 no 5 pp 509ndash517 2010

[81] L Timmers S K Lim I E Hoefer et al ldquoHuman mesenchy-mal stem cell-conditioned medium improves cardiac functionfollowing myocardial infarctionrdquo Stem Cell Research vol 6 no3 pp 206ndash214 2011

[82] Y Y Yeh H G Ozer A M Lehman et al ldquoCharacterizationof CLL exosomes reveals a distinct microRNA signature andenhanced secretion by activation of BCR signalingrdquo Blood vol125 no 21 pp 3297ndash3305 2015

[83] C Emanueli A I Shearn G D Angelini and S SahooldquoExosomes and exosomalmiRNAs in cardiovascular protectionand repairrdquo Vascular Pharmacology vol 71 pp 24ndash30 2015

[84] H Valadi K Ekstrom A Bossios M Sjostrand J J Leeand J O Lotvall ldquoExosome-mediated transfer of mRNAs andmicroRNAs is a novel mechanism of genetic exchange betweencellsrdquo Nature Cell Biology vol 9 no 6 pp 654ndash659 2007

[85] A Waldenstrom and G Ronquist ldquoRole of exosomes inmyocardial remodelingrdquoCirculation Research vol 114 no 2 pp315ndash324 2014

[86] E Hergenreider S Heydt K Treguer et al ldquoAtheroprotectivecommunication between endothelial cells and smooth musclecells through miRNAsrdquo Nature Cell Biology vol 14 no 3 pp249ndash256 2012

[87] J Halkein S P Tabruyn M Ricke-Hoch et al ldquoMicroRNA-146a is a therapeutic target and biomarker for peripartumcardiomyopathyrdquo The Journal of Clinical Investigation vol 123no 5 pp 2143ndash2154 2013

[88] T S Chen R C Lai M M Lee A B H Choo C N Leeand S K Lim ldquoMesenchymal stem cell secretes microparticlesenriched in pre-microRNAsrdquoNucleic Acids Research vol 38 no1 pp 215ndash224 2010

[89] R C Lai F Arslan M M Lee et al ldquoExosome secreted byMSC reduces myocardial ischemiareperfusion injuryrdquo StemCell Research vol 4 no 3 pp 214ndash222 2010

[90] J Oswald S Boxberger B Joslashrgensen et al ldquoMesenchymal stemcells can be differentiated into endothelial cells in vitrordquo STEMCELLS vol 22 no 3 pp 377ndash384 2004

[91] R Thakker and P Yang ldquoMesenchymal stem cell therapy forcardiac repairrdquo Current Treatment Options in CardiovascularMedicine vol 16 no 7 p 323 2014

[92] R-Z Lin RMoreno-Luna B ZhouW T Pu and JMMelero-Martin ldquoEqual modulation of endothelial cell function by fourdistinct tissue-specific mesenchymal stem cellsrdquo Angiogenesisvol 15 no 3 pp 443ndash455 2012


[93] S G Ball C A Shuttleworth and C M Kielty ldquoVascularendothelial growth factor can signal through platelet-derivedgrowth factor receptorsrdquo Journal of Cell Biology vol 177 no 3pp 489ndash500 2007

[94] S A Gomes E B Rangel C Premer et al ldquoS-nitrosogluta-thione reductase (GSNOR) enhances vasculogenesis by mes-enchymal stem cellsrdquo Proceedings of the National Academy ofSciences of the United States of America vol 110 no 8 pp 2834ndash2839 2013

[95] M Wang Y Su H Sun et al ldquoInduced endothelial differenti-ation of cells from a murine embryonic mesenchymal cell lineC3H10T12 by angiogenic factors in vitrordquo Differentiation vol79 no 1 pp 21ndash30 2010

[96] M-Y Chen P-C Lie Z-L Li and X Wei ldquoEndothelialdifferentiation of Whartonrsquos jelly-derived mesenchymal stemcells in comparison with bone marrow-derived mesenchymalstem cellsrdquo Experimental Hematology vol 37 no 5 pp 629ndash640 2009

[97] Q-W He Y-P Xia S-C Chen et al ldquoAstrocyte-derived sonichedgehog contributes to angiogenesis in brain microvascu-lar endothelial cells via RhoAROCK pathway after oxygen-glucose deprivationrdquoMolecular Neurobiology vol 47 no 3 pp976ndash987 2013

[98] N Wang R Zhang S-J Wang et al ldquoVascular endothelialgrowth factor stimulates endothelial differentiation from mes-enchymal stem cells via Rhomyocardin-related transcriptionfactormdasha signaling pathwayrdquo The International Journal of Bio-chemistry amp Cell Biology vol 45 no 7 pp 1447ndash1456 2013

[99] H Lin A Shabbir M Molnar et al ldquoAdenoviral expression ofvascular endothelial growth factor splice variants differentiallyregulate bone marrow-derived mesenchymal stem cellsrdquo Jour-nal of Cellular Physiology vol 216 no 2 pp 458ndash468 2008

[100] D Wang J S Park J S F Chu et al ldquoProteomic profilingof bone marrow mesenchymal stem cells upon transforminggrowth factor 1205731 stimulationrdquo The Journal of Biological Chem-istry vol 279 no 42 pp 43725ndash43734 2004

[101] K Abnaof NMallela GWalenda et al ldquoTGF-120573 stimulation inhuman and murine cells reveals commonly affected biologicalprocesses and pathways at transcription levelrdquo BMC SystemsBiology vol 8 article 55 2014

[102] J-W Lee S-H Lee Y-J Youn et al ldquoA randomized open-label multicenter trial for the safety and efficacy of adultmesenchymal stem cells after acute myocardial infarctionrdquoJournal of Korean Medical Science vol 29 no 1 pp 23ndash31 2014

[103] J M Hare J E Fishman G Gerstenblith et al ldquoComparisonof allogeneic vs autologous bonemarrow-derivedmesenchymalstem cells delivered by transendocardial injection in patientswith ischemic cardiomyopathy the POSEIDON randomizedtrialrdquoThe Journal of the American Medical Association vol 308no 22 pp 2369ndash2379 2012

[104] J M Hare J H Traverse T D Henry et al ldquoA random-ized double-blind placebo-controlled dose-escalation study ofintravenous adult human mesenchymal stem cells (prochymal)after acute myocardial infarctionrdquo Journal of the AmericanCollege of Cardiology vol 54 no 24 pp 2277ndash2286 2009

[105] A Chullikana A SMajumdar S Gottipamula et al ldquoRandom-ized double-blind phase III study of intravenous allogeneicmesenchymal stromal cells in acute myocardial infarctionrdquoCytotherapy vol 17 no 3 pp 250ndash261 2015

[106] L R Gao Y Chen N K Zhang et al ldquoIntracoronary infusionof Whartonrsquos jelly-derived mesenchymal stem cells in acute

myocardial infarction double-blind randomized controlledtrialrdquo BMCMedicine vol 13 article 162 2015

[107] A W Heldman D L DiFede J E Fishman et al ldquoTransendo-cardial mesenchymal stem cells andmononuclear bonemarrowcells for ischemic cardiomyopathy the TAC-HFT randomizedtrialrdquoThe Journal of the American Medical Association vol 311no 1 pp 62ndash73 2014

[108] B Trachtenberg D L Velazquez A R Williams et alldquoRationale and design of the transendocardial injection ofautologous human cells (bone marrow or mesenchymal) inchronic ischemic left ventricular dysfunction and heart failuresecondary to myocardial infarction (TAC-HFT) trial a ran-domized double-blind placebo-controlled study of safety andefficacyrdquo American Heart Journal vol 161 no 3 pp 487ndash4932011

[109] A B Mathiasen A A Qayyum E Jorgensen et al ldquoBonemarrow-derived mesenchymal stromal cell treatment inpatients with severe ischaemic heart failure a randomizedplacebo-controlled trial (MSC-HF trial)rdquo European HeartJournal vol 36 pp 1744ndash1753 2015

[110] A B Mathiasen E Jorgensen A A Qayyum M Haack-Sorensen A Ekblond and J Kastrup ldquoRationale and design ofthe first randomized double-blind placebo-controlled trial ofintramyocardial injection of autologous bone-marrow derivedMesenchymal Stromal Cells in chronic ischemic Heart Failure(MSC-HF Trial)rdquo American Heart Journal vol 164 no 3 pp285ndash291 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


tissue and peripheral blood or neonatal birth-associatedtissues like Whartonrsquos Jelly and placenta [9]

Bone-marrow-derivedMSCs (BM-MSCs) can be isolatedfrom bone marrow aspiration which are among the mostfrequently used types in regenerative studies However theway to get BM-MSCs is accompanied by a risk of infec-tion and is painful for patients which means that findingalternatives is essential in clinical practice Fortunately otherthan bone marrow several kinds of MSCs have been isolatedsuccessfully For example peripheral blood-derived MSCs(PB-MSCs) can be isolated frommononuclear cells of periph-eral blood [10] Adipose-derived MSCs are usually obtainedfrom adipose samples by enzymatic digestion [11] MoreoverWhartonrsquos Jelly of umbilical cord and placenta are consideredto be convenient and readily alternatives to bone marrow[12 13] MSCs derived fromWhartonrsquos Jelly have the weakestexpression of histocompatibility complex class I genes [14]and immune-related genes [15] while they do not expressmajor histocompatibility complex class II genes [14] whichmeans that Whartonrsquos Jelly-derived MSCs are promisingsource for tissue regeneration in clinical application

MSCs are partly differentiated progenitor cells containingmultilineage stem cells and there are no specific and reliablemarkers for defining native MSCs Isolation and purificationof MSCs usually involve density gradient centrifugation orimmunophenotyping [16] The phenotype of MSCs is deter-mined by certain surface markers including CD49a (alpha-1 integrin) CD73 (ecto-51015840-nucleotidase) CD105 (endoglin)MSC antigen-1 CD271 (adapalene) CD29 CD44 CD90 andCD106 (vascular cell adhesionmolecule-1) but lack of CD34CD45 CD14 HLA-DR CD19 and CD79 [17 18] Howeverno specific single marker can be used to identify MSCs fromother kinds of cell types The lack of specific MSCs markershas thwarted the attempts to categorize these kind of stemcells in vivo [19]The specific genotype and proteonomic pro-filesrsquo analysis of multipotential MSCs clones has been carriedout to further elucidate the characterization of MSCs whichare promising to understand themechanisms formaintainingor regulating those cells from different sources [20] CD106 ismainly expressed on blood vessel endothelium which also isan important marker for MSCs [13] Moreover MSCs withhigh expression of transmembrane protein cadherin-2 (N-cadherin) have revealed a higher probability to differentiateinto cardiomyocytes which indicates that MSCs can improveheart function directly [21] The unique subpopulation ofMSCs possessing specific differentiation potency may con-tribute to designed therapeutic strategies

3 Therapeutic Application of MSCs forVascular Regeneration

Despite advances in medical treatment cardiovascular dis-eases (CVDs) are still major causes of adult death Stemcell-based therapy in the treatment of ischemic diseases isa fast-growing field that has been proven effective and safe[22] MSCs can transdifferentiate into all cell lineages ofthree germ layers including blood vessel cells arising frommesodermal tissue which means that it is an attractive cell

Resident CSCs

MSCs

Cardiomyocyte

Cytokines

Endothelium and cardiomyocyte

Tran

sdiffe

rentia

tion

Proli

ferati

on

Paracrine

Activation

Figure 1 MSCs mediated therapy for myocardial infarction (MI)MSCs therapy could enhance heart function by (1) transdifferenti-ation into cardiomyocytes or endothelial cells (ECs) to replace thedamage tissue and promote angiogenesis respectively (2) releasingsoluble autocrineparacrine factors thereby activating endogenousadult cells involved in cells renewalprotection and neovasculariza-tion and (3) stimulating endogenous resident cardiac stem cells(CSCs) proliferation and differentiation by paracrine soluble factors

type for stem cell-based therapy for treatment of CVDs[23] The therapeutic contribution of MSCs to tissue repairincludes direct differentiation into injured cells includingcardiomyocytes smooth muscle cell and ECs presentingcytokines in the microenvironment and stimulating endoge-nous stem cell differentiation (Figure 1) The most necessaryproperty of MSCs for treatment of ischemic diseases is theirdifferentiation potential toward vascular phenotypes whichcan be identified by specific markers or functional assays

31 The Application of MSCs for Ischemia Heart DiseaseTherapy Among the various forms of ischemic diseasesischemic heart disease is a serious disease caused by theimbalance between myocardial oxygen supply and demand[24 25] MSCs transplantation could promote myocardiumrepair by stimulating angiogenesis and MSCs have emergedas a promising cell type for ischemic heart disease therapyboth in small and large animal models [26] For examplethe intravenously injected MSCs derived from rat fetal heartfor treatment ofmyocardial ischemia has achieved significantimprovement in cardiac function [27] The injected cellswere found to express ECs and smooth muscle cells (SMCs)markers suggesting that MSCs can transdifferentiate intoSMCs and ECs This result was also confirmed in largeanimal study In a swine model of chronic ischemic car-diomyopathy the engraftedMSCs were found to differentiateinto cardiomyocytes SMCs and endothelium [28] More-over the efficacy of intramyocardial injection of autologousMSCs has been confirmed in a clinical trial [29] Here wesummarized the use of MSCs in clinical trials in CVDstreatment according to httpsclinicaltrialsgov (Table 1) Anumber of trials are focused on the safety and efficacy ofautologousallogeneic MSCs transplantation The results of






signaling


[102]



of infarct size


[103]





[29]




after AMI[104]



blood vessels


patients

[105]




[106]





[107 108]




vessels



function

[109 110]
















2120572(PGF2120572) [61 62]





(a) (b)

(c) (d)

(e) (f)

(g)














Cytokines




Paracrine effects


Angiogenesis

Endogenous ECs





6 Conclusions







Acknowledgments


References






































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






signaling


[102]



of infarct size


[103]





[29]




after AMI[104]



blood vessels


patients

[105]




[106]





[107 108]




vessels



function

[109 110]
















2120572(PGF2120572) [61 62]





(a) (b)

(c) (d)

(e) (f)

(g)














Cytokines




Paracrine effects


Angiogenesis

Endogenous ECs





6 Conclusions







Acknowledgments


References






































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology











2120572(PGF2120572) [61 62]





(a) (b)

(c) (d)

(e) (f)

(g)














Cytokines




Paracrine effects


Angiogenesis

Endogenous ECs





6 Conclusions







Acknowledgments


References






































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


(a) (b)

(c) (d)

(e) (f)

(g)














Cytokines




Paracrine effects


Angiogenesis

Endogenous ECs





6 Conclusions







Acknowledgments


References






































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology













Cytokines




Paracrine effects


Angiogenesis

Endogenous ECs





6 Conclusions







Acknowledgments


References






































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































































1-treated human


























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




























Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Review Article Proangiogenic Features of Mesenchymal Stem...

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