review article therapeutic potential of stem cells...

Review ArticleTherapeutic Potential of Stem Cells Strategy forCardiovascular Diseases

Chang Youn Lee1 Ran Kim2 Onju Ham3 Jihyun Lee2 Pilseog Kim2 Seokyeon Lee2

Sekyung Oh4 Hojin Lee5 Minyoung Lee6 Jongmin Kim7 and Woochul Chang2

1Department of Integrated Omics for Biomedical Sciences Graduate School Yonsei University 50 Yonsei-ro Seodaemun-guSeoul 120-759 Republic of Korea2Department of Biology Education College of Education Pusan National University Busan 609-735 Republic of Korea3Institute for Bio-Medical Convergence Catholic Kwandong University International St Maryrsquos Hospital Incheon 404-834Republic of Korea4Department of Neurology and Neurological Sciences Stanford University School of Medicine Stanford CA 94305 USA5Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA6Department of Molecular Physiology College of Pharmacy Kyungpook National University Daegu 702-701 Republic of Korea7Department of Life Systems Sookmyung Womenrsquos University 52 Hyochangwon-gil Yongsan-gu Seoul 140-742 Republic of Korea

Correspondence should be addressed to Woochul Chang wchang1975pusanackr

Received 31 May 2016 Revised 9 August 2016 Accepted 20 September 2016

Academic Editor Wenbin Liang

Copyright copy 2016 Chang Youn Lee et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Despite development of medicine cardiovascular diseases (CVDs) are still the leading cause of mortality andmorbidity worldwideOver the past 10 years various stem cells have been utilized in therapeutic strategies for the treatment of CVDs CVDs arecharacterized by a broad range of pathological reactions including inflammation necrosis hyperplasia and hypertrophy Howeverthe causes of CVDs are still unclear While there is a limit to the currently available target-dependent treatments the therapeuticpotential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects anti-inflammatory activityand immunomodulatory capacity Various studies have recently reported increased therapeutic potential of transplantationof microRNA- (miRNA-) overexpressing stem cells or small-molecule-treated cells In addition to treatment with drugs oroverexpressed miRNA in stem cells stem cell-derived extracellular vesicles also have therapeutic potential because they can deliverthe stem cell-specific RNA and protein into the host cell thereby improving cell viability Here we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy

1 Introduction

Cardiovascular diseases (CVDs) are a major cause of mor-bidity and mortality that have a significant impact on healthcare systems and financial and social consequences It isestimated that CVDs will be responsible for 233 millionglobal cardiovascular deaths worldwide in 2030 [1] CVDsinclude diseases that have different causes and characteristics[2] There is a state of acute conditions such as myocardialinfarction and chronic diseases induced by genetic mutations[3] Classic treatments of CVDs such as physical surgery andmedicinal treatment are not sufficient to recover damaged

cardiovascular tissue and instead only delay the progressionof CVDs

Stem cells including embryonic stem cells (ESCs) adultstem cells and induced pluripotent stem cells (iPSCs) areuseful in the field of regenerative medicine because theyhave pluripotency and self-renewal In addition stem cellshave beneficial effects such as paracrine effects [4 5] anti-inflammatory activity [6 7] and immunomodulatory capac-ity [8] However transplantation of stem cells for treatment ofheart disease is hampered by their potential for differentiationinto host cell types such as cardiac cells or blood vesselcells to hinder cardiac function by causing arrhythmia [9]

Hindawi Publishing CorporationStem Cells InternationalVolume 2016 Article ID 4285938 10 pageshttpdxdoiorg10115520164285938

2 Stem Cells International

and their low therapeutic effects and viability under theharsh conditions of damaged tissue [10] To overcome theseproblems establishment of new strategies is needed forpriming of stem cells

Interestingly it has recently been reported that miRNAsmall molecules and extracellular vesicles can modulate thebiological activity of stem cells such as their survival [1112] migration [13] and differentiation [14ndash16] According toreports they have been attracting attention owing to theirpotential to overcome the limitations associated with stemcell therapy Moreover a previous study of miRNA smallmolecules and extracellular vesicles demonstrated that theywere effective in the treatment of CVDs Based on thesestudies the stem cell therapy can contribute to treatment ofCVDs

In this review we describe the state of stem cell therapyfor the treatment of CVDs and evaluate the potential for theuse of miRNA or stem cell-derived extracellular vesicles

2 Cardiovascular Diseases and Stem Cells

21 Cause of CVDs CVDs include a range of major clin-ical disease conditions such as cardiomyopathy hyperten-sive heart failure valvular heart disease peripheral arterialdisease and coronary artery disease [25 26] Senescenceand male typically raise hazards of CVDs and are primarycriteria used to classify risk evaluation [27 28] CVDs arestrongly connected to lifestyle age and gender with alcoholand tobacco consumption physical inactivity psychosocialfactor diet and obesity and increased blood pressure beingmajor factors [28] In addition psychosocial risk elementsincluding low socioeconomic status deficiency of socialsupport stress depression anxiety disorder and hostilitycontribute to development of CVDs [28ndash34] Familial preva-lence of CVDs is another major risk factors [28] Nutrientdeficiency including low vitamin D levels also plays a rolein CVDs pathogenesis [35] Several studies have shownthat vitamin D affects heart function through regulation ofhormonal systems including the parathyroid hormone andrenin-angiotensin system [36 37] Vitamin D has also beenshown to affect the cell cycle of cardiomyocytes to inhibitcardiac cell proliferation and to protect the structure andfunction of cardiomyocytes [35 38 39] Hypertension is themost common CVD leading to a growing risk of strokemyocardial infarction and heart and renal failures [40]Previous clinical tests have indicated that decreased bloodpressure reduces the outbreak of CVDs such as stroke andheart attack [40]There have been various efforts to overcomeCVDs in the past few decades [41] Despite advancedmedicaland surgical trials there are still no effective therapiesfor treatment of CVDs [42 43] Unlike other organs therecuperative ability of heart is limited for treatment of injuredcardiac tissue [43] Heart transplantation can be utilized as alast resort to treat CVDs but the approach is expensive andextremely limited for patients because of their comorbiditiesor poor supply of donor organs [43]

22 Embryonic Stem Cell Therapy for CVDs Recent stud-ies have suggested that stem cell therapies target cardiac

regeneration in CVDs [42 43] Application of stem cellsto therapeutic devices and methods may lead to effec-tive and rapid myocardium regeneration and eventuallyaffect cardiovascular morbidity and mortality [44] Thereare different types of stem cells such as embryonic stemcells adult stem cells and induced pluripotent stem cellsfor treatment of CVDs (Table 1) Previous studies havedemonstrated therapeutic effects of ESCs differentiated intocardiomyocytes [17] and endothelial cells [18] for myocardialinfarction umbilical-cord-blood-derived MSCs for dilatedcardiomyopathy [19] bone-marrow-derived-MSCs for cellu-lar cardiomyoplasty [20] and iPSCs [21] and iPSCs-derivedcardiovascular progenitor cells [22] endothelial progenitorcells (EPCs) [23] and cardiac stem cells [24] for myocardialinfarction

221 Therapeutic Characteristics of ESCs ESCs are pluripo-tent cells derived from the inner cell mass and infinitely repli-cate without senescence maintaining their undifferentiatedstate [45] This cell population is called ESCs and followsirreversible process of differentiation to become specialized[44 46] ESCs have pluripotency with the capacity ofdifferentiation into approximately 210 different cell typesmaking them an up-and-coming stem cell source for cell-based tissue engineering [44] ESCs can be differentiatedinto cardiomyocytes endothelial cells and vascular smoothmuscle cells [17 18 47 48] Owing to their potential for usein the treatment of CVDs efforts for stem cell therapy havebeen concentrated on the differentiation of human ESCs intothe cardiac lineage directly [44 49]

222 Using ESCs for Myocardial Regeneration Therapy Inprevious studies undifferentiated ESCs or ESCs differenti-ated into cardiomyocytes endothelial cells or vascular cellswere directly injected into animal CVDs models [17 18 50]Treatment with those ESC-derived cells showed beneficialeffects such as improvement of cardiac regeneration andremodeling and increased myocardial performance [1 17 1850]Therapeutic effects of the differentiated cells aremediatedthrough cell engraftment and proliferation and paracrineeffects [1 51 52] Recent studies have suggested that geneticand epigenetic regulations of cardiomyocytes differentiationare new approaches to inducing a cardiac lineage for stemcell therapy [43] Deletion or knockdown of microRNA(miRNA) a small regulator of gene expression brings aboutdysregulation of morphogenesis electrical conduction andhypertrophy of heart and the cell cycle of cardiocytes[14 43 53] Ivey et al demonstrated that miR-1 and miR-133 can control the ability to differentiate into the cardiaclineage inmouse and human ESCs [53] Moreover epigeneticmodification can regulate ESCs differentiation and geneticcontrol [43]Weber et al suggested that histone deacetylationis involved in cardiovascular development through targetregulation of hey bHLH as major effector in Notch signaling[54] Although ESCs have considerable potential for directdifferentiation into cardiac lineage in various models severallimitations hinder their clinical applications [41]The greatestlimitation is that research using ESCs is hampered by ethicalissues that prevent their actual clinical applications [41 55]

Stem Cells International 3

Table1Ap

plicationof

stem

cells

fortherapy

ofCV

Ds

Dise

asem

odel

Stem

celltype

Delivery

route

Dosea

ndfollo

w-up

duratio

nOutcomes

Reference

RatM

IES

C-CM

sIntram

yocardialtransfer

15times106

8weeks

Observatio

nof

graft

edcardiomyocytessurvivalproliferatio

nmaturation

alignm

entandform

inggapjunctio

nswith

hostcardiactiss

ue[17]

Mou

seMI

ESC-

ECs

Intram

yocardialtransfer

1times106

8weeks

Approp

riatepatte

rnso

fend

othelialgenee

xpression

functio

nalvessels

form

ationin

vivoand

cardiacfun

ctionim

provem

ent

[18]

Mou

seDCM

UCB

-MSC

sIntram

yocardialtransfer

15times106

4weeks

Improvem

ento

fcardiac

functio

nby

antia

poptosis

anti-inflammation

and

proang

iogenesis

[19]

Mou

secellu

lar

cardiomyoplasty

BM-M

SCs

Intram

yocardialtransfer

5ndash10times106

4ndash8weeks

Engraft

edhM

SCsfrom

adultB

Min

them

yocardium

todifferentiateinto

cardiomyocytes

[20]

Mou

seMI

iPSC

sIntram

yocardialtransfer

1times105

2weeks

Improved

iPSC

smaintenance

throug

him

proved

functio

nandcell

proliferatio

nin

infarctedmyocardium

[21]

Mou

seMI

iPSC

-CPC

sIntram

yocardialtransfer

2times105

2ndash4weeks

Exertio

nof

protectiv

eeffecton

LVremod

elingby

paracrinee

ffectsthrou

ghenhanced

angiogenesisandaugm

entednetworking

intheinfarcted

milieu

[22]

RatM

IEP

SsIntram

yocardialtransfer

1times106

7weeks

Increase

ofregion

alwallm

otionanddecrease

ofventric

ular

dimensio

nin

left

ventric

le[23]

RatM

ICS

CsIntram

yocardialtransfer

5times106

2ndash4weeks

Redu

ctionof

ejectio

nfractio

nfractio

nalsho

rteningandinfractedsiz

eofthe

leftventric

le[24]

BMbon

emarrowC

MscardiomyocytesCP

Cscardiovascularp

rogenitorc

ellsCS

Cscardiac

stem

cellsD

CMdilatedcardiomyopathyEC

sendo

thelialcellsE

PCsendo

thelialprogenitorc

ells

ESC

embryonic

stem

cellhhu

maniPS

Cindu

cedpluripotentstem

cellMImyocardialinfarction

MSC

smesenchym

alste

mcellsand

UCB

umbilicalcord

bloo

d


Moreover treatment with ESCs poses the risk of immunore-jection because of differences in genome information amongpatients [41 56]

23 Adult Stem Cell Therapy for CVDs

231 Therapeutic Characteristics of MSCs In adult bodiestissues and organs contain a small cell subpopulation withthe capacity for self-maintenance through the potential toproliferate indefinitely and the ability to form an extendedfamily of daughter cells [57 58]These cells are widely knownas adult stem cells [7] Mesenchymal stem cells (MSCs) arefound in most of adult tissues including bone marrow andadipose tissues [58 59] The nonhematopoietic cells can bedifferentiated and modified in vitro to present phenotypesof cardiomyocytes and vascular endothelial cells [58] Inaddition MSCs are able to produce and secrete a broadvariety of cytokines chemokines and growth factors forenhancing neovascularization attenuating fibrosis in heartand recovering cardiac functions [4 5 60] Accordingly it ispossible thatMSCs could be a therapeutic cell source with thecapacity to repair injured tissue in CVDs

232 Treatments of Myocardial Diseases by Using MSCsBone-marrow-derived MSCs (BM-MSCs) have been widelyreported as a promising therapeutic strategy for CVDs[61] These cells can differentiate into cardiomyocytes andendothelial cells [20 61] Many studies have indicatedthat BM-MSCs possess therapeutic effects in heart diseasessuch as myocardial infarction diabetic cardiomyopathyand dilated cardiomyopathy [61ndash63] and BM-MSCs arenow considered one of the most attractive adult stem cellpopulations for cardiovascular repair [61 64] Cai et alshowed that BM-MSCs cocultured with neonatal rat ventric-ular cardiomyocytes prevented isoproterenol-induced typicalhypertrophic characteristics of cardiomyocytes in in vitroand in vivo studies [61] Moreover interplay of BM-MSCswith cardiomyocytes produced synergistic effects on VEGFsecretion [61] Today many studies showed that paracrinefactors such as VEGF bFGF and IGF-1 play an essentialtherapeutic role [4] Tang et al demonstrated that autolo-gous BM-MSCs transplantation in rat MI model improvedvascular regeneration and cardiac performance throughparacrine effect of VEGF bFGF and SDF-1 [5] Ohnishi etal also found conditioned medium of BM-MSCs affectedthe antiproliferation of cardiac fibroblasts via expressingparacrine antifibrotic effects of MMPs [60] Adipose tissue-derived MSCs (AD-MSCs) have become an attractive ther-apeutic cell source [65] because they are easily expanded invitro and express the same cell surface markers as BM-MSCs[65 66] Moreover injected AD-MSCs have been shown todifferentiate toward a cardiogenic phenotype [67] and reducethe infracted size exhibiting a powerful and persisting angio-genic potential [65 68] Siciliano et al reported on plasticityof human AD-MSCs and their phenotypical modificationin cardiac-specific microenvironments [65] They also indi-cated that human AD-MSCs cocultured with cardiospheres-conditioned media changed toward a cardiacendothelialmuscular-like phenotype in response to regulation of the

expression of cardiogenic markers and induction of theactivation of intracellular survival signaling pathways [65]Umbilical-cord-blood-derivedMSCs (UCB-MSCs) are a newxenogeneic stem cell therapy source for CVDs [19]The newlyproposed cell sourcemay be optimum for CVDs because theyhave a low immunogenicity and a large change of cardiomy-ocyte reprogramming of UCB-MSCs in comparison withxenogeneic stem cells [19 69ndash71] In additionUCB-MSCs areeasily obtained through low-invasive surgery without raisingethical issues demonstrating their promising clinical appli-cation [19] Gong et al demonstrated that intramyocardialgrafts of human UCB-MSCs promote cardiac function viamechanisms of antiapoptosis anti-inflammation and proan-giogenesis in cardiomyopathy of cTnTR141W transgenic mice[19] They also found that UCB-MSCs derived conditionedmedium protects H9C2 cells from apoptosis in hypoxiccondition by paracrine effects in vitro [19]

233 Treatments of Myocardial Diseases by Using Other StemCells (CPCs EPCs) The tissue-specific stem cells were foundin several tissues such as skeletal muscle brain fat livergastrointestinal tract and epidermis These stem cells aredifferentiated into specific tissue cells and contribute tomain-taining tissue homeostasis Interestingly the tissue-specificstem cells were found in heart [72] Heart was not known tobe able to self-regenerate before the establishment of cardiacprogenitor cells (CPCs) Since then cardiac progenitor cellshave been reported on therapeutic potential in CVDs

Beltrami et al reported on Linminus c-KitPOS cells in CPCsThey are self-renewing and multipotent and have colonyforming ability [72] Injected CPCs into the ischemic heartcan be differentiated into cardiomyocytes reconstruct heartand induce new blood vessel They suggest that CPCs torepair the heart provide a new opportunity However CPCspresent in very small amounts in the heart and require in vitroexpansion of a few weeks [73]

In 1997 Asahara et al reported that isolated CD34POS

cells are endothelial progenitor cells which are separatefrom peripheral blood [74] EPCs also have capacity ofdifferentiation into endothelial cells and angiogenesis Forthat reason EPC was noted in the study for treating variousischemic injury Kawamoto et al studied effects of heartregeneration by transplantation of EPCs into rat MI heart in4 weeks after transplantation [23] According to this paperthe effect of regeneration is caused by angiogenesis which ispromoted by transplanted EPCs into ischemic damage area

Another strategy is reported based on the stimulation ofthe EPCs in vivo for treating ischemic disease Oikonomou etal reported that 26 patients with heart disease have improvedblood vessel function after administration of atorvastatin for4 weeks by increasing circulated EPCs [75]

Transplantation of EPC has benefit for treatment ofdisease but we need to concern about immune rejectionin the allograft because therapy using EPCs is based onthe autograft method Therefore we need to overcome thislimitation for transplantation into damaged area

24 iPSCs as a Source of Cell Therapies for CVDs In 2006iPSCs were established by Takahashi and Yamanaka by


Category Direct differentiation iPSC reprogramming

Differentiation capacity Limited-fibroblast self-renewal Easily scalable

Time consuming for differentiation Short Long (over 10 days)

Cell fate stable Unclear Stable

Tumor risk Unclear tumor risk duringreprogramming Teratoma and overgrowth

Clinical application Lack of differentiated cells fortransplantation Various results in vivo and in vitro

LimitationLow conversion efficiency

heterogeneous cell population andrisk of viral action in clinical trial

Proliferation capacity cell typediversity senescence and limited cell

type diversity

Somatic cells Cardiac lineage cells

Reprogramming

iPSCs

DifferentiationDifferentiation


(a) Direct differentiation (b) iPSCs reprogramming

Figure 1 Strategies for differentiation from somatic cells into cardiac lineage cells

Somatic cells

Reprogramming

iPSCs

(A-1) Integrating vectors(i) Retrolentiviruses

(a) Oct4 Sox2 Klf4 and c-Myc

(A-2) Plasmid or lentiviral vectors(i) CreloxP system

(A) Genetic transduction

(B) Integrated-free methods(i) Plasmid

(ii) Recombinant proteins(iii) Small molecules(iv) MicroRNAs(v) Minicircle DNA vectors

(C) DNA-free methods(i) Sendai virus-based vectors

(ii) Modified mRNAs(iii) Recombinant proteins or

cell extracts

Figure 2 Two ways for inducing pluripotent cells from somatic cells

reprogramming mouse fibroblasts through overexpressionof four specific transcription factors Oct34 Sox2 c-Mycand Klf4 [76] Since this breakthrough various opportunitiesfor application have been reported in cell therapy modelingof new diseases and studies of complex genetic featuresand allelic variations as substrates for drug in toxicitydifferentiation and regenerative medicine therapies and intherapeutic screening [77 78] In addition using the iPSCsit is possible to differentiate into patient- and disease-specificcell types Thus using iPSC is one of the tools for treatmentof the patients [79 80] However many considerationsincluding the optimal materials for reprogramming highcost safety and efficient derivation still remained regardingusing iPSCs for clinical applications [81] Thus it is essentialto understand the following events after the activation ofreprogramming factors for transplantation of iPSCs for a safeway

241 Methods for Differentiation from iPSCs to Cardiomy-ocytes Recently various efficient methods for inducing dif-ferentiation into cardiac lineage cells using iPSCs or direct

reprogramming (Figure 1) iPSCs have been tried to usegenetic transduction or integrated-free methods Using viralvector for reprogramming has higher efficiency than usingintegrated-free methods but safety is lower than usingintegrated-free methods (Figure 2) [82] Another methodfor differentiation into cardiac lineage cells is direct dif-ferentiation One of the protocols for direct differentiationis overexpression of combined cardiac-specific transcriptionfactors such as GATA4 Mef2c and Tbx5 (GMT) [83 84] orGMT and Hand2 [85] Another method is using miRNAsor small molecules without lineage-specific transcriptionfactors overexpression of miRNAs 1 133 208 and 499 iseffective to increase the capacity of direct differentiation intocardiac lineage cells [86] chemically definedmedium (CDM)containing three components is also reported that can inducedifferentiation into cardiomyocytes [87] Recently Hou etal also reported that treatment of seven small moleculesinto cells can generate iPSCs [88] Direct differentiation intocardiac-specific lineage may provide the therapeutic strategyfor cardiac regeneration however it needs to improve the lowefficiency of differentiation into the cardiac lineage cells [84]


242 Treatment of CVDs by Transplanted iPSCs iPSCs havecharacters like embryonic stem cells (ESCs)mdashpluripotencyand self-renewalmdashso that iPSCs can be provided to betransplanted into damaged tissue or organ [89] Masumotoet al reported cardiac regeneration by transplantation ofengineered human iPSC as a cardiac tissue sheet (hiPSC-CTSs) into rat heart [90] They checked that heart functionwas improved and survival of transplanted cells was over 40cells Rojas et al performed transplantation of iPSCs with fib-rinogen into heart of myocardial injury model [21] Althoughheart function was recovered by transplantation of iPSCsinto damaged heart they suggested transplantation of iPSC-derived cardiomyocytes is more relevant for clinical trial Inaddition the problems of transplantation of iPSCs includ-ing tumorigenicity immunogenicity and genomic instabilityhave been reported [88 91ndash94] Recently transplantationof differentiated cells into tissue-specific lineage is reportedto overcome the aforementioned problems Funakoshi et alreported transplantation of iPSC-derived cardiomyocyte andthey tried to optimize condition for transplantation [95]and Ja et al showed the effects of the transplantation ofiPSC-derived human cardiac progenitor cells improved heartfunction [22] They suggested that the improvement of heartfunction is caused by angiogenesis and interstitial networkingof damaged heart

25 Cell-Free Therapeutic Strategy for CVDs Extracellularvesicles have been reported tomodulate a variety of biologicalactions in the cells such as proliferation migration apopto-sis and differentiation Stem cell-derived extracellular vesi-cles especially have potent cardiac protection regenerationand angiogenic properties In addition to affordable benefitsit is well known the vesicles can be used to communicatewith other cells and control level of protein expressionThustransplantation of extracellular vesicles has the potential asa novel cell-free therapy for treatment of CVDs which hasvarious advantages to overcome the limitations related to thecell-based therapeutics

251 Treatment of CVDs by Extracellular Vesicles-DerivedStem Cells Various reports have emphasized the effective-ness of secretion factors during treatment of heart diseaseusing stem cells Paracrine effect is one of the benefitsby transplantation of stem cells into the damaged areacausing secretion of various cytokines and growth factors[4 5] Recently many studies have investigated cell-derivedextracellular vesicles and they have been shown to exertpositive effects on a variety of cellular activities such asantiapoptosismigration differentiation and cell recruitment[96] In fact extracellular vesicles have a biologic function ofcommunication between the cells and recipient cells Severalstudies have reported that the extracellular vesicles containedvarious factors including nucleic acids cytokines growth fac-tor andmiRNAs [97ndash99] Lai et al reported that extracellularvesicles can promote repair of damaged heart by myocardialischemiareperfusion injury [100] They have demonstratedthat the exosome was contained in the stem cell conditionedmedia so that it contributed to the cardiac protection Leeet al demonstrated that mesenchymal stromal cell-derived

exosomes (MEX) inhibited vascular remodeling and hypoxicpulmonary hypertension [101] They also demonstrated thatMEX inhibit the inflammatory response and cell proliferationof vascular pulmonary hypertension in animal models Theysuggested that the reason of the advantages was based on thedownregulation ofmiR-17 cluster and stat3 signaling inMEX-treated vessel cells Khan et al reported that ESC-derivedexosome promoted the repair of ischemic myocardium [102]Therapeutic potential of ESC-derived exosome stimulatesCPCs activity including survival cell cycle progression andproliferation by overexpression of ESC-specific miR-294Furthermore therapeutic effects of CPCs-derived exosomeshave been reported [103] Vrijsen et al reported that CPCs-derived exosomes promote cell migration in vitro woundassay [104] According to their report CPCs-derived exo-somes include EMMPRIN and MMP to induce endothelialcell migration Chen et al reported a myocardial infarctionprotective effect of the CPCs-derived exosome [105] CPCs-derived exosome contains higher level of miR-451 so itcan protect H9C2 cells from oxidative stress by inhibitingcaspase-3 and caspase-7 activation

Although there are a lot of experiments that have studiedtransplantation of extracellular vesicles which have beneficialeffect in treating CVD in vitro and in vivo we still need toconsider side effects on other organs appropriate amountfor transplantation and compatibility for clinical practices inhuman Therefore more researches which targeted safety touse for therapeutic approaches using extracellular vesicles arerequired in future clinical trials

26 Limitations of Stem Cell and Cell-Free Therapy Strategiesfor CVDs Stem cell therapy should be more considered forefficient clinical application in CVDs Despite the many pos-itive efforts for stem cell therapy it has still some problemssuch as low efficiency immune rejection and difficulty incontrol of stem cell behavior in vivo In addition adminis-tered stem cells often do not show effective integration orpersistence in the heart tissues and trigger tumor formation[106]

On the other hand the cell-free therapy was proposed asa means to avoid such a problem which can occur in stemcell therapy However the short half-life is a problem of thecell-free therapy because the proteins and nucleic acids arerapidly biodegradable in vivo as amain component [107ndash109]For this reason cell-free therapy must be administered morefrequently Moreover disease specificity biodistribution andpersistency of the cell-free factors must be validated beforeclinical application [110]

3 Conclusions

In this review we focus on the strategy for treatment of CVDsby transplantation of stem cells Transplantation of stem cellsincluding ESCs adult stem cells and iPSCs can promotetissue regeneration of damaged area Stem cells have specificcharacters such as self-renewal and pluripotency In additionstem cells secrete paracrine factors so transplantation ofwhich shows beneficial effects Stem cell-derived vesiclescan stimulate the cell activity by transferring beneficial


materials including the stem cell-specific transcription factorand miRNA to the damaged tissue Thus transplantationof vesicle can contribute to recovery in damaged area Inaddition treatment of additional materials such as miRNAor small molecules for promoting differentiation of stem cellsinto specific cell types can improve therapeutic effects fortreatment of CVDs

Although stem cell therapy has problems such as lowsurvival rate after transplantation into harsh condition andstill needs to overcome these problem stem cell therapyand cell-free based therapy have potential to improve heartfunction after CVDs

Competing Interests

The authors report no conflict of interests in this work

Authorsrsquo Contributions

Chang Youn Lee Ran Kim and Onju Ham contributedequally to this work

Acknowledgments

This research was supported by a 2-Year Research Grant ofPusan National University

References

[1] T H Chao I C Chen S Y Tseng and Y H Li ldquoPluripotentstem cell therapy in ischemic cardiovascular diseaserdquo ZhonghuaMinguo Xin Zang Xue Hui Za Zhi vol 30 no 5 pp 365ndash3742014

[2] P Elliott B Andersson E Arbustini et al ldquoClassification ofthe cardiomyopathies a position statement from the EuropeanSociety of Cardiology Working Group on Myocardial andPericardial Diseasesrdquo European Heart Journal vol 29 no 2 pp270ndash276 2008

[3] I Y Chen E Matsa and J C Wu ldquoInduced pluripotent stemcells at the heart of cardiovascular precision medicinerdquo NatureReviews Cardiology vol 13 no 6 pp 333ndash349 2016

[4] M Gnecchi Z Zhang A Ni and V J Dzau ldquoParacrine mech-anisms in adult stem cell signaling and therapyrdquo CirculationResearch vol 103 no 11 pp 1204ndash1219 2008

[5] Y L Tang Q Zhao X Qin et al ldquoParacrine action enhancesthe effects of autologousmesenchymal stem cell transplantationon vascular regeneration in rat model of myocardial infarctionrdquoThe Annals of Thoracic Surgery vol 80 no 1 pp 229ndash237 2005

[6] R H Lee A A Pulin M J Seo et al ldquoIntravenous hMSCsimprove myocardial infarction in mice because cells embolizedin lung are activated to secrete the anti-inflammatory proteinTSG-6rdquo Cell Stem Cell vol 5 no 1 pp 54ndash63 2009

[7] J Y Oh M K Kim M S Shin et al ldquoThe anti-inflammatoryand anti-angiogenic role of mesenchymal stem cells in cornealwound healing following chemical injuryrdquo STEM CELLS vol26 no 4 pp 1047ndash1055 2008

[8] A Uccelli L Moretta and V Pistoia ldquoMesenchymal stem cellsin health and diseaserdquo Nature Reviews Immunology vol 8 no9 pp 726ndash736 2008

[9] H J Hwang W Chang B-W Song et al ldquoAntiarrhythmicpotential of mesenchymal stem cell is modulated by hypoxic

environmentrdquo Journal of the American College of Cardiologyvol 60 no 17 pp 1698ndash1706 2012

[10] Y-J Geng ldquoMolecular mechanisms for cardiovascular stemcell apoptosis and growth in the hearts with atheroscleroticcoronary disease and ischemic heart failurerdquo Annals of the NewYork Academy of Sciences vol 1010 pp 687ndash697 2003

[11] W Chang C Y Lee J-H Park et al ldquoSurvival of hypoxichuman mesenchymal stem cells is enhanced by a positivefeedback loop involving mir-210 and hypoxia-inducible factor1rdquo Journal of Veterinary Science vol 14 no 1 pp 69ndash76 2013

[12] R Damoiseaux S P Sherman J A Alva C Peterson and AD Pyle ldquoIntegrated chemical genomics reveals modifiers ofsurvival in human embryonic stem cellsrdquo STEM CELLS vol 27no 3 pp 533ndash542 2009

[13] W Chang R Kim S I Park et al ldquoEnhanced healing of ratcalvarial bone defects with hypoxic conditioned medium frommesenchymal stem cells through increased endogenous stemcell migration via regulation of ICAM-1 targeted-microRNA-221rdquoMolecules and Cells vol 38 no 7 pp 643ndash650 2015

[14] Y Zhao E Samal and D Srivastava ldquoSerum response factorregulates a muscle-specific microRNA that targets Hand2 dur-ing cardiogenesisrdquoNature vol 436 no 7048 pp 214ndash220 2005

[15] J-F Chen E M Mandel J M Thomson et al ldquoThe role ofmicroRNA-1 andmicroRNA-133 in skeletalmuscle proliferationand differentiationrdquoNature Genetics vol 38 no 2 pp 228ndash2332006

[16] H Sadek B Hannack E Choe et al ldquoCardiogenic smallmolecules that enhance myocardial repair by stem cellsrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 105 no 16 pp 6063ndash6068 2008

[17] O Caspi I Huber I Kehat et al ldquoTransplantation of humanembryonic stem cell-derived cardiomyocytes improvesmyocar-dial performance in infarcted rat heartsrdquo Journal of the Ameri-can College of Cardiology vol 50 no 19 pp 1884ndash1893 2007

[18] 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

[19] X Gong P Wang Q Wu S Wang L Yu and G WangldquoHuman umbilical cord blood derived mesenchymal stem cellsimprove cardiac function in cTnTR141W transgenic mouse ofdilated cardiomyopathyrdquo European Journal of Cell Biology vol95 no 1 pp 57ndash67 2016

[20] C Toma M F Pittenger K S Cahill B J Byrne and P DKessler ldquoHuman mesenchymal stem cells differentiate to a car-diomyocyte phenotype in the adult murine heartrdquo Circulationvol 105 no 1 pp 93ndash98 2002

[21] S V Rojas A Martens R Zweigerdt et al ldquoTransplantationeffectiveness of induced pluripotent stem cells is improved bya fibrinogen biomatrix in an experimental model of ischemicheart failurerdquo Tissue Engineering Part A vol 21 no 13-14 pp1991ndash2000 2015

[22] P M M Ja Q Miao N G Zhen Tee et al ldquoiPSC-derived hu-man cardiac progenitor cells improve ventricular remod-elling via angiogenesis and interstitial networking of infarctedmyocardiumrdquo Journal of Cellular and Molecular Medicine vol20 no 2 pp 323ndash332 2016

[23] A Kawamoto H-C Gwon H Iwaguro et al ldquoTherapeuticpotential of ex vivo expanded endothelial progenitor cells formyocardial ischemiardquo Circulation vol 103 no 5 pp 634ndash6372001


[24] F Song F Hua H Li et al ldquoCardiac stem cell transplan-tation with 23541015840-tetrahydroxystilbehe-2-O-120573-D-glucosideimproves cardiac function in rat myocardial infarction modelrdquoLife Sciences vol 158 pp 37ndash45 2016

[25] M J Sarnak A S Levey A C Schoolwerth et al ldquoKidneydisease as a risk factor for development of cardiovasculardisease a statement from the American Heart AssociationCouncils on Kidney in Cardiovascular Disease High BloodPressure Research Clinical Cardiology and Epidemiology andPreventionrdquo Hypertension vol 42 no 5 pp 1050ndash1065 2003

[26] M Lafeber W Spiering F L Visseren and D E GrobbeeldquoMultifactorial prevention of cardiovascular disease in patientswith hypertension the cardiovascular polypillrdquo Current Hyper-tension Reports vol 18 no 5 article 40 2016

[27] R M Conroy K Pyorala A P Fitzgerald et al ldquoEstimationof ten-year risk of fatal cardiovascular disease in Europe theSCOREprojectrdquoEuropeanHeart Journal vol 24 no 11 pp 987ndash1003 2003

[28] J Perk G De Backer H Gohlke et al ldquoEuropean Guidelines oncardiovascular disease prevention in clinical practice (version2012) The Fifth Joint Task Force of the European Societyof Cardiology and Other Societies on Cardiovascular DiseasePrevention in Clinical Practice (constituted by representativesof nine societies and by invited experts)rdquo European HeartJournal vol 33 no 13 pp 1635ndash1701 2012

[29] A R Rahimi J A Spertus K J Reid S M Bernheim and HM Krumholz ldquoFinancial barriers to health care and outcomesafter acute myocardial infarctionrdquo The Journal of the AmericanMedical Association vol 297 no 10 pp 1063ndash1072 2007

[30] F Mookadam and H M Arthur ldquoSocial support and itsrelationship to morbidity and mortality after acute myocardialinfarction systematic overviewrdquo Archives of Internal Medicinevol 164 no 14 pp 1514ndash1518 2004

[31] E D Eaker L M Sullivan M Kelly-Hayes R B DrsquoAgostinoSr and E J Benjamin ldquoMarital status marital strain and riskof coronary heart disease or total mortality the FraminghamOffspring Studyrdquo Psychosomatic Medicine vol 69 no 6 pp509ndash513 2007

[32] R Rugulies ldquoDepression as a predictor for coronary heartdisease A review and meta-analysisrdquo American Journal ofPreventive Medicine vol 23 no 1 pp 51ndash61 2002

[33] J W Smoller M H Pollack S Wassertheil-Smoller et alldquoPanic attacks and risk of incident cardiovascular events amongpostmenopausal women in the Womenrsquos Health InitiativeObservational StudyrdquoArchives of General Psychiatry vol 64 no10 pp 1153ndash1160 2007

[34] Y Chida and A Steptoe ldquoThe association of anger and hostilitywith future coronary heart disease a meta-analytic reviewof prospective evidencerdquo Journal of the American College ofCardiology vol 53 no 11 pp 936ndash946 2009

[35] M Liu X Li R Sun Y Zeng S Chen and P Zhang ldquoVitaminD nutritional status and the risk for cardiovascular disease(review)rdquo Experimental andTherapeutic Medicine vol 11 no 4pp 1189ndash1193 2016

[36] P Andersson E Rydberg and R Willenheimer ldquoPrimaryhyperparathyroidism and heart diseasemdasha reviewrdquo EuropeanHeart Journal vol 25 no 20 pp 1776ndash1787 2004

[37] W Xiang J Kong S Chen et al ldquoCardiac hypertrophy in vita-min D receptor knockout mice role of the systemic and cardiacrenin-angiotensin systemsrdquo American Journal of PhysiologymdashEndocrinology and Metabolism vol 288 no 1 pp E125ndashE1322005

[38] T D OrsquoConnell J E Berry A K Jarvis M J Somerman and RU Simpson ldquo1 25-Dihydroxyvitamin D3 regulation of cardiacmyocyte proliferation and hypertrophyrdquo American Journal ofPhysiology vol 272 no 4 part 2 pp H1759ndashH1769 1997

[39] S Bae S S Singh H Yu J Y Lee B R Cho and P MKang ldquoVitamin D signaling pathway plays an important rolein the development of heart failure after myocardial infarctionrdquoJournal of Applied Physiology vol 114 no 8 pp 979ndash987 2013

[40] E G Nabel ldquoCardiovascular diseaserdquoTheNew England Journalof Medicine vol 349 no 1 pp 60ndash72 2003

[41] Q Sun Z Zhang and Z Sun ldquoThe potential and challengesof using stem cells for cardiovascular repair and regenerationrdquoGenes and Diseases vol 1 no 1 pp 113ndash119 2014

[42] M L Moreira P da Costa Medeiros S A de Souza BGutfilen and P H Rosado-de-Castro ldquoIn vivo tracking of celltherapies for cardiac diseases with nuclearmedicinerdquo StemCellsInternational vol 2016 Article ID 3140120 15 pages 2016

[43] H S Bernstein and D Srivastava ldquoStem cell therapy for cardiacdiseaserdquo Pediatric Research vol 71 no 4 part 2 pp 491ndash4992012

[44] R K Sharma D J Voelker R Sharma and H K ReddyldquoUnderstanding the application of stem cell therapy in car-diovascular diseasesrdquo Stem Cells and Cloning Advances andApplications vol 5 no 1 pp 29ndash37 2012

[45] M Yousefi V Hajihoseini W Jung et al ldquoEmbryonic stemcell interactomics the beginning of a long road to biologicalfunctionrdquo Stem Cell Reviews and Reports vol 8 no 4 pp 1138ndash1154 2012

[46] D C Kraushaar and K Zhao ldquoThe epigenomics of embryonicstem cell differentiationrdquo International Journal of BiologicalSciences vol 9 no 10 pp 1134ndash1144 2013

[47] S G Nir R David M Zaruba W-M Franz and J Itskovitz-Eldor ldquoHuman embryonic stem cells for cardiovascular repairrdquoCardiovascular Research vol 58 no 2 pp 313ndash323 2003

[48] AMWobus GWallukat and J Hescheler ldquoPluripotentmouseembryonic stem cells are able to differentiate into cardiomy-ocytes expressing chronotropic responses to adrenergic andcholinergic agents and Ca2+ channel blockersrdquo Differentiationvol 48 no 3 pp 173ndash182 1991

[49] S S Wong and H S Bernstein ldquoCardiac regeneration usinghuman embryonic stem cells producing cells for future ther-apyrdquo Regenerative Medicine vol 5 no 5 pp 763ndash775 2010

[50] Q Xiong L Ye P Zhang et al ldquoBioenergetic and functionalconsequences of cellular therapy activation of endogenouscardiovascular progenitor cellsrdquo Circulation Research vol 111no 4 pp 455ndash468 2012

[51] C Freund and C L Mummery ldquoProspects for pluripotentstem cell-derived cardiomyocytes in cardiac cell therapy and asdisease modelsrdquo Journal of Cellular Biochemistry vol 107 no 4pp 592ndash599 2009

[52] H EbeltM Jungblut Y Zhang et al ldquoCellular cardiomyoplastyimprovement of left ventricular function correlates with therelease of cardioactive cytokinesrdquo Stem Cells vol 25 no 1 pp236ndash244 2007

[53] K N Ivey A Muth J Arnold et al ldquoMicroRNA regulation ofcell lineages in mouse and human embryonic stem cellsrdquo CellStem Cell vol 2 no 3 pp 219ndash229 2008

[54] DWeber J Heisig S Kneitz EWolf M Eilers andM GesslerldquoMechanisms of epigenetic and cell-type specific regulation ofHey target genes in ES cells and cardiomyocytesrdquo Journal ofMolecular and Cellular Cardiology vol 79 pp 79ndash88 2015


[55] E C Perin Y-J Geng and J T Willerson ldquoAdult stem celltherapy in perspectiverdquo Circulation vol 107 no 7 pp 935ndash9382003

[56] M Murata S Tohyama and K Fukuda ldquoImpacts of recentadvances in cardiovascular regenerative medicine on clinicaltherapies and drug discoveryrdquo Pharmacology and Therapeuticsvol 126 no 2 pp 109ndash118 2010

[57] E Fuchs and J A Segre ldquoStem cells a new lease on liferdquo Cellvol 100 no 1 pp 143ndash155 2000

[58] R Poulsom M R Alison S J Forbes and N A Wright ldquoAdultstem cell plasticityrdquoThe Journal of Pathology vol 197 no 4 pp441ndash456 2002

[59] P Bianco M Riminucci S Gronthos and P G Robey ldquoBonemarrow stromal stem cells nature biology and potentialapplicationsrdquo STEM CELLS vol 19 no 3 pp 180ndash192 2001

[60] S Ohnishi H Sumiyoshi S Kitamura and N Nagaya ldquoMes-enchymal stem cells attenuate cardiac fibroblast proliferationand collagen synthesis through paracrine actionsrdquo FEBS Lettersvol 581 no 21 pp 3961ndash3966 2007

[61] B Cai X Tan Y Zhang et al ldquoMesenchymal stem cells andcardiomyocytes interplay to prevent myocardial hypertrophyrdquoStem Cells Translational Medicine vol 4 no 12 pp 1425ndash14352015

[62] R S Ripa M Haack-Soslashrensen Y Wang et al ldquoBone marrowderived mesenchymal cell mobilization by granulocyte-colonystimulating factor after acute myocardial infarction resultsfrom the Stem Cells in Myocardial Infarction (STEMMI) trialrdquoCirculation vol 116 no 11 supplement pp I24ndashI30 2007

[63] V Volarevic N Arsenijevic M L Lukic and M StojkovicldquoConcise review mesenchymal stem cell treatment of thecomplications of diabetes mellitusrdquo Stem Cells vol 29 no 1 pp5ndash10 2011

[64] J-Y Hahn H-J Cho H-J Kang et al ldquoPre-treatment ofmesenchymal stem cells with a combination of growth fac-tors enhances gap junction formation cytoprotective effecton cardiomyocytes and therapeutic efficacy for myocardialinfarctionrdquo Journal of the American College of Cardiology vol51 no 9 pp 933ndash943 2008

[65] C Siciliano I Chimenti M Ibrahim et al ldquoCardiosphereconditioned media influence the plasticity of human medi-astinal adipose tissue-derived mesenchymal stem cellsrdquo CellTransplantation vol 24 no 11 pp 2307ndash2322 2015

[66] D A De Ugarte Z Alfonso P A Zuk et al ldquoDifferentialexpression of stem cell mobilization-associated molecules onmulti-lineage cells from adipose tissue and bone marrowrdquoImmunology Letters vol 89 no 2-3 pp 267ndash270 2003

[67] A Schaffler and C Buchler ldquoConcise review adipose tissue-derived stromal cellsmdashbasic and clinical implications for novelcell-based therapiesrdquo StemCells vol 25 no 4 pp 818ndash827 2007

[68] L Casteilla V Planat-Benard B Cousin P Laharrague and PBourin ldquoVascular and endothelial regenerationrdquo Current StemCell Research andTherapy vol 5 no 2 pp 141ndash144 2010

[69] I Perea-Gil M Monguio-Tortajada C Galvez-Monton ABayes-Genis F E Borras and S Roura ldquoPreclinical evaluationof the immunomodulatory properties of cardiac adipose tissueprogenitor cells using umbilical cord blood mesenchymal stemcells a direct comparative studyrdquo BioMed Research Interna-tional vol 2015 Article ID 439808 9 pages 2015

[70] M Lee S Y Jeong J Ha et al ldquoLow immunogenicity ofallogeneic human umbilical cord blood-derived mesenchymalstem cells in vitro and in vivordquo Biochemical and BiophysicalResearch Communications vol 446 no 4 pp 983ndash989 2014

[71] G Yannarelli V Dayan N Pacienza C-J Lee J Medinand A Keating ldquoHuman umbilical cord perivascular cellsexhibit enhanced cardiomyocyte reprogramming and cardiacfunction after experimental acute myocardial infarctionrdquo CellTransplantation vol 22 no 9 pp 1651ndash1666 2013

[72] A P Beltrami L Barlucchi D Torella et al ldquoAdult cardiac stemcells are multipotent and support myocardial regenerationrdquoCell vol 114 no 6 pp 763ndash776 2003

[73] P Oettgen A J Boyle S P Schulman and J M Hare ldquoCardiacstem cell therapy Need for optimization of efficacy and safetymonitoringrdquo Circulation vol 114 no 4 pp 353ndash358 2006

[74] T Asahara T Murohara A Sullivan et al ldquoIsolation of putativeprogenitor endothelial cells for angiogenesisrdquo Science vol 275no 5302 pp 964ndash967 1997

[75] E Oikonomou G Siasos M Zaromitidou et al ldquoAtorvastatintreatment improves endothelial function through endothelialprogenitor cells mobilization in ischemic heart failure patientsrdquoAtherosclerosis vol 238 no 2 pp 159ndash164 2015

[76] K Takahashi and S Yamanaka ldquoInduction of pluripotent stemcells from mouse embryonic and adult fibroblast cultures bydefined factorsrdquo Cell vol 126 no 4 pp 663ndash676 2006

[77] F Gonzalez S Boue and J C Izpisua Belmonte ldquoMethods formaking induced pluripotent stem cells Reprogramming a lacarterdquo Nature Reviews Genetics vol 12 no 4 pp 231ndash242 2011

[78] M Csobonyeiova S Polak and L Danisovic ldquoPerspectivesof induced pluripotent stem cells for cardiovascular systemregenerationrdquo Experimental Biology and Medicine vol 240 no5 pp 549ndash556 2015

[79] K Narsinh K H Narsinh and J C Wu ldquoDerivation of humaninduced pluripotent stem cells for cardiovascular disease mod-elingrdquo Circulation Research vol 108 no 9 pp 1146ndash1156 2011

[80] K Schenke-Layland K E Rhodes E Angelis et al ldquoRepro-grammed mouse fibroblasts differentiate into cells of the car-diovascular and hematopoietic lineagesrdquo Stem Cells vol 26 no6 pp 1537ndash1546 2008

[81] Z Tong A Solanki A Hamilos et al ldquoApplication of bioma-terials to advance induced pluripotent stem cell research andtherapyrdquoThe EMBO Journal vol 34 no 8 pp 987ndash1008 2015

[82] F Jia K D Wilson N Sun et al ldquoA nonviral minicircle vectorfor deriving human iPS cellsrdquo Nature Methods vol 7 no 3 pp197ndash199 2010

[83] M Ieda J-D Fu P Delgado-Olguin et al ldquoDirect reprogram-ming of fibroblasts into functional cardiomyocytes by definedfactorsrdquo Cell vol 142 no 3 pp 375ndash386 2010

[84] J X Chen M Krane M-A Deutsch et al ldquoInefficient repro-gramming of fibroblasts into cardiomyocytes using Gata4Mef2c and Tbx5rdquo Circulation Research vol 111 no 1 pp 50ndash55 2012

[85] K Song Y-J Nam X Luo et al ldquoHeart repair by reprogram-ming non-myocytes with cardiac transcription factorsrdquoNaturevol 485 no 7400 pp 599ndash604 2012

[86] T M Jayawardena B Egemnazarov E A Finch et alldquoMicroRNA-mediated in vitro and in vivo direct reprogram-ming of cardiac fibroblasts to cardiomyocytesrdquo CirculationResearch vol 110 no 11 pp 1465ndash1473 2012

[87] P W Burridge E Matsa P Shukla et al ldquoChemically definedgeneration of human cardiomyocytesrdquo Nature Methods vol 11no 8 pp 855ndash860 2014

[88] P Hou Y Li X Zhang et al ldquoPluripotent stem cells inducedfrom mouse somatic cells by small-molecule compoundsrdquoScience vol 341 no 6146 pp 651ndash654 2013


[89] X Lu and T Zhao ldquoClinical therapy using iPSCs hopes andchallengesrdquo Genomics Proteomics amp Bioinformatics vol 11 no5 pp 294ndash298 2013

[90] H Masumoto T Ikuno M Takeda et al ldquoHuman iPS cell-engineered cardiac tissue sheets with cardiomyocytes andvascular cells for cardiac regenerationrdquo Scientific Reports vol4 article 6716 2014

[91] M Tong Z Lv L Liu et al ldquoMice generated from tetraploidcomplementation competent iPS cells show similar develop-mental features as those from ES cells but are prone totumorigenesisrdquo Cell Research vol 21 no 11 pp 1634ndash1637 2011

[92] K Okita T Ichisaka and S Yamanaka ldquoGeneration ofgermline-competent induced pluripotent stem cellsrdquo Naturevol 448 no 7151 pp 313ndash317 2007

[93] T Zhao Z-N Zhang Z Rong and Y Xu ldquoImmunogenicity ofinduced pluripotent stem cellsrdquo Nature vol 474 no 7350 pp212ndash216 2011

[94] C E Pasi A Dereli-Oz S Negrini et al ldquoGenomic instabilityin induced stem cellsrdquoCell Death andDifferentiation vol 18 no5 pp 745ndash753 2011

[95] S Funakoshi K Miki T Takaki et al ldquoEnhanced engraftmentproliferation and therapeutic potential in heart using opti-mized human iPSC-derived cardiomyocytesrdquo Scientific Reportsvol 6 Article ID 19111 2016

[96] S El Andaloussi I Mager X O Breakefield and M J AWood ldquoExtracellular vesicles biology and emerging therapeu-tic opportunitiesrdquoNature Reviews Drug Discovery vol 12 no 5pp 347ndash357 2013

[97] M Simons and G Raposo ldquoExosomesmdashvesicular carriers forintercellular communicationrdquo Current Opinion in Cell Biologyvol 21 no 4 pp 575ndash581 2009

[98] S Mathivanan and R J Simpson ldquoExoCarta a compendiumof exosomal proteins and RNArdquo Proteomics vol 9 no 21 pp4997ndash5000 2009

[99] M Mittelbrunn C Gutierrez-Vazquez C Villarroya-Beltri etal ldquoUnidirectional transfer of microRNA-loaded exosomesfrom T cells to antigen-presenting cellsrdquo Nature Communica-tions vol 2 no 1 article 282 2011

[100] 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

[101] C Lee S A Mitsialis M Aslam et al ldquoExosomes mediate thecytoprotective action ofmesenchymal stromal cells on hypoxia-induced pulmonary hypertensionrdquo Circulation vol 126 no 22pp 2601ndash2611 2012

[102] M Khan E Nickoloff T Abramova et al ldquoEmbryonic stemcell-derived exosomes promote endogenous repairmechanismsand enhance cardiac function following myocardial infarctionrdquoCirculation Research vol 117 no 1 pp 52ndash64 2015

[103] L Barile V Lionetti E Cervio et al ldquoExtracellular vesicles fromhuman cardiac progenitor cells inhibit cardiomyocyte apoptosisand improve cardiac function after myocardial infarctionrdquoCardiovascular Research vol 103 no 4 pp 530ndash541 2014

[104] K R Vrijsen J P G Sluijter M W L Schuchardt et alldquoCardiomyocyte progenitor cell-derived exosomes stimulatemigration of endothelial cellsrdquo Journal of Cellular andMolecularMedicine vol 14 no 5 pp 1064ndash1070 2010

[105] L Chen Y Wang Y Pan et al ldquoCardiac progenitor-derivedexosomes protect ischemic myocardium from acute ischemiareperfusion injuryrdquo Biochemical and Biophysical Research Com-munications vol 431 no 3 pp 566ndash571 2013

[106] R C Lai T S Chen and S K Lim ldquoMesenchymal stem cellexosome a novel stem cell-based therapy for cardiovasculardiseaserdquo Regenerative Medicine vol 6 no 4 pp 481ndash492 2011

[107] P Yde B Mengel M H Jensen S Krishna and A TrusinaldquoModeling the NF-120581B mediated inflammatory response pre-dicts cytokine waves in tissuerdquo BMC Systems Biology vol 5article 115 2011

[108] A Khosravi C M Cutler M H Kelly et al ldquoDeterminationof the elimination half-life of fibroblast growth factor-23rdquo TheJournal of Clinical Endocrinology amp Metabolism vol 92 no 6pp 2374ndash2377 2007

[109] Y Takahashi M Nishikawa H Shinotsuka et al ldquoVisualizationand in vivo tracking of the exosomes of murine melanomaB16-BL6 cells in mice after intravenous injectionrdquo Journal ofBiotechnology vol 165 no 2 pp 77ndash84 2013

[110] L Biancone S Bruno M C Deregibus C Tetta and GCamussi ldquoTherapeutic potential of mesenchymal stem cell-derived microvesiclesrdquo Nephrology Dialysis Transplantationvol 27 no 8 pp 3037ndash3042 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


and their low therapeutic effects and viability under theharsh conditions of damaged tissue [10] To overcome theseproblems establishment of new strategies is needed forpriming of stem cells

Interestingly it has recently been reported that miRNAsmall molecules and extracellular vesicles can modulate thebiological activity of stem cells such as their survival [1112] migration [13] and differentiation [14ndash16] According toreports they have been attracting attention owing to theirpotential to overcome the limitations associated with stemcell therapy Moreover a previous study of miRNA smallmolecules and extracellular vesicles demonstrated that theywere effective in the treatment of CVDs Based on thesestudies the stem cell therapy can contribute to treatment ofCVDs

In this review we describe the state of stem cell therapyfor the treatment of CVDs and evaluate the potential for theuse of miRNA or stem cell-derived extracellular vesicles

2 Cardiovascular Diseases and Stem Cells

21 Cause of CVDs CVDs include a range of major clin-ical disease conditions such as cardiomyopathy hyperten-sive heart failure valvular heart disease peripheral arterialdisease and coronary artery disease [25 26] Senescenceand male typically raise hazards of CVDs and are primarycriteria used to classify risk evaluation [27 28] CVDs arestrongly connected to lifestyle age and gender with alcoholand tobacco consumption physical inactivity psychosocialfactor diet and obesity and increased blood pressure beingmajor factors [28] In addition psychosocial risk elementsincluding low socioeconomic status deficiency of socialsupport stress depression anxiety disorder and hostilitycontribute to development of CVDs [28ndash34] Familial preva-lence of CVDs is another major risk factors [28] Nutrientdeficiency including low vitamin D levels also plays a rolein CVDs pathogenesis [35] Several studies have shownthat vitamin D affects heart function through regulation ofhormonal systems including the parathyroid hormone andrenin-angiotensin system [36 37] Vitamin D has also beenshown to affect the cell cycle of cardiomyocytes to inhibitcardiac cell proliferation and to protect the structure andfunction of cardiomyocytes [35 38 39] Hypertension is themost common CVD leading to a growing risk of strokemyocardial infarction and heart and renal failures [40]Previous clinical tests have indicated that decreased bloodpressure reduces the outbreak of CVDs such as stroke andheart attack [40]There have been various efforts to overcomeCVDs in the past few decades [41] Despite advancedmedicaland surgical trials there are still no effective therapiesfor treatment of CVDs [42 43] Unlike other organs therecuperative ability of heart is limited for treatment of injuredcardiac tissue [43] Heart transplantation can be utilized as alast resort to treat CVDs but the approach is expensive andextremely limited for patients because of their comorbiditiesor poor supply of donor organs [43]

22 Embryonic Stem Cell Therapy for CVDs Recent stud-ies have suggested that stem cell therapies target cardiac

regeneration in CVDs [42 43] Application of stem cellsto therapeutic devices and methods may lead to effec-tive and rapid myocardium regeneration and eventuallyaffect cardiovascular morbidity and mortality [44] Thereare different types of stem cells such as embryonic stemcells adult stem cells and induced pluripotent stem cellsfor treatment of CVDs (Table 1) Previous studies havedemonstrated therapeutic effects of ESCs differentiated intocardiomyocytes [17] and endothelial cells [18] for myocardialinfarction umbilical-cord-blood-derived MSCs for dilatedcardiomyopathy [19] bone-marrow-derived-MSCs for cellu-lar cardiomyoplasty [20] and iPSCs [21] and iPSCs-derivedcardiovascular progenitor cells [22] endothelial progenitorcells (EPCs) [23] and cardiac stem cells [24] for myocardialinfarction

221 Therapeutic Characteristics of ESCs ESCs are pluripo-tent cells derived from the inner cell mass and infinitely repli-cate without senescence maintaining their undifferentiatedstate [45] This cell population is called ESCs and followsirreversible process of differentiation to become specialized[44 46] ESCs have pluripotency with the capacity ofdifferentiation into approximately 210 different cell typesmaking them an up-and-coming stem cell source for cell-based tissue engineering [44] ESCs can be differentiatedinto cardiomyocytes endothelial cells and vascular smoothmuscle cells [17 18 47 48] Owing to their potential for usein the treatment of CVDs efforts for stem cell therapy havebeen concentrated on the differentiation of human ESCs intothe cardiac lineage directly [44 49]

222 Using ESCs for Myocardial Regeneration Therapy Inprevious studies undifferentiated ESCs or ESCs differenti-ated into cardiomyocytes endothelial cells or vascular cellswere directly injected into animal CVDs models [17 18 50]Treatment with those ESC-derived cells showed beneficialeffects such as improvement of cardiac regeneration andremodeling and increased myocardial performance [1 17 1850]Therapeutic effects of the differentiated cells aremediatedthrough cell engraftment and proliferation and paracrineeffects [1 51 52] Recent studies have suggested that geneticand epigenetic regulations of cardiomyocytes differentiationare new approaches to inducing a cardiac lineage for stemcell therapy [43] Deletion or knockdown of microRNA(miRNA) a small regulator of gene expression brings aboutdysregulation of morphogenesis electrical conduction andhypertrophy of heart and the cell cycle of cardiocytes[14 43 53] Ivey et al demonstrated that miR-1 and miR-133 can control the ability to differentiate into the cardiaclineage inmouse and human ESCs [53] Moreover epigeneticmodification can regulate ESCs differentiation and geneticcontrol [43]Weber et al suggested that histone deacetylationis involved in cardiovascular development through targetregulation of hey bHLH as major effector in Notch signaling[54] Although ESCs have considerable potential for directdifferentiation into cardiac lineage in various models severallimitations hinder their clinical applications [41]The greatestlimitation is that research using ESCs is hampered by ethicalissues that prevent their actual clinical applications [41 55]


Table1Ap

plicationof

stem

cells

fortherapy

ofCV

Ds

Dise

asem

odel

Stem

celltype

Delivery

route

Dosea

ndfollo

w-up

duratio

nOutcomes

Reference

RatM

IES

C-CM

sIntram

yocardialtransfer

15times106

8weeks

Observatio

nof

graft


nmaturation

alignm

entandform

inggapjunctio

nswith

hostcardiactiss

ue[17]

Mou

seMI

ESC-

ECs

Intram

yocardialtransfer

1times106

8weeks

Approp

riatepatte

rnso

fend

othelialgenee

xpression

functio

nalvessels

form

ationin

vivoand

cardiacfun

ctionim

provem

ent

[18]

Mou

seDCM

UCB

-MSC

sIntram

yocardialtransfer

15times106

4weeks

Improvem

ento

fcardiac

functio

nby

antia

poptosis

anti-inflammation

and

proang

iogenesis

[19]

Mou

secellu

lar

cardiomyoplasty

BM-M

SCs

Intram

yocardialtransfer

5ndash10times106

4ndash8weeks

Engraft

edhM

SCsfrom

adultB

Min

them

yocardium

todifferentiateinto

cardiomyocytes

[20]

Mou

seMI

iPSC

sIntram

yocardialtransfer

1times105

2weeks

Improved

iPSC

smaintenance

throug

him

proved

functio

nandcell

proliferatio

nin

infarctedmyocardium

[21]

Mou

seMI

iPSC

-CPC

sIntram

yocardialtransfer

2times105

2ndash4weeks

Exertio

nof

protectiv

eeffecton

LVremod

elingby

paracrinee

ffectsthrou

ghenhanced

angiogenesisandaugm

entednetworking

intheinfarcted

milieu

[22]

RatM

IEP

SsIntram

yocardialtransfer

1times106

7weeks

Increase

ofregion

alwallm

otionanddecrease

ofventric

ular

dimensio

nin

left

ventric

le[23]

RatM

ICS

CsIntram

yocardialtransfer

5times106

2ndash4weeks

Redu

ctionof

ejectio

nfractio

nfractio

nalsho


eofthe

leftventric

le[24]

BMbon

emarrowC

MscardiomyocytesCP

Cscardiovascularp

rogenitorc

ellsCS

Cscardiac

stem

cellsD


sendo

thelialcellsE

PCsendo

thelialprogenitorc

ells

ESC

embryonic

stem

cellhhu

maniPS

Cindu

cedpluripotentstem


MSC

smesenchym

alste

mcellsand

UCB

umbilicalcord

bloo

d
























type diversity


Reprogramming

iPSCs





Somatic cells

Reprogramming

iPSCs









cell extracts













3 Conclusions





Competing Interests




Acknowledgments


References


























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Table1Ap

plicationof

stem

cells

fortherapy

ofCV

Ds

Dise

asem

odel

Stem

celltype

Delivery

route

Dosea

ndfollo

w-up

duratio

nOutcomes

Reference

RatM

IES

C-CM

sIntram

yocardialtransfer

15times106

8weeks

Observatio

nof

graft


nmaturation

alignm

entandform

inggapjunctio

nswith

hostcardiactiss

ue[17]

Mou

seMI

ESC-

ECs

Intram

yocardialtransfer

1times106

8weeks

Approp

riatepatte

rnso

fend

othelialgenee

xpression

functio

nalvessels

form

ationin

vivoand

cardiacfun

ctionim

provem

ent

[18]

Mou

seDCM

UCB

-MSC

sIntram

yocardialtransfer

15times106

4weeks

Improvem

ento

fcardiac

functio

nby

antia

poptosis

anti-inflammation

and

proang

iogenesis

[19]

Mou

secellu

lar

cardiomyoplasty

BM-M

SCs

Intram

yocardialtransfer

5ndash10times106

4ndash8weeks

Engraft

edhM

SCsfrom

adultB

Min

them

yocardium

todifferentiateinto

cardiomyocytes

[20]

Mou

seMI

iPSC

sIntram

yocardialtransfer

1times105

2weeks

Improved

iPSC

smaintenance

throug

him

proved

functio

nandcell

proliferatio

nin

infarctedmyocardium

[21]

Mou

seMI

iPSC

-CPC

sIntram

yocardialtransfer

2times105

2ndash4weeks

Exertio

nof

protectiv

eeffecton

LVremod

elingby

paracrinee

ffectsthrou

ghenhanced

angiogenesisandaugm

entednetworking

intheinfarcted

milieu

[22]

RatM

IEP

SsIntram

yocardialtransfer

1times106

7weeks

Increase

ofregion

alwallm

otionanddecrease

ofventric

ular

dimensio

nin

left

ventric

le[23]

RatM

ICS

CsIntram

yocardialtransfer

5times106

2ndash4weeks

Redu

ctionof

ejectio

nfractio

nfractio

nalsho


eofthe

leftventric

le[24]

BMbon

emarrowC

MscardiomyocytesCP

Cscardiovascularp

rogenitorc

ellsCS

Cscardiac

stem

cellsD


sendo

thelialcellsE

PCsendo

thelialprogenitorc

ells

ESC

embryonic

stem

cellhhu

maniPS

Cindu

cedpluripotentstem


MSC

smesenchym

alste

mcellsand

UCB

umbilicalcord

bloo

d
























type diversity


Reprogramming

iPSCs





Somatic cells

Reprogramming

iPSCs









cell extracts













3 Conclusions





Competing Interests




Acknowledgments


References


























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
























type diversity


Reprogramming

iPSCs





Somatic cells

Reprogramming

iPSCs









cell extracts













3 Conclusions





Competing Interests




Acknowledgments


References


























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









3 Conclusions





Competing Interests




Acknowledgments


References


























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Competing Interests




Acknowledgments


References


























































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

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