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Hatzistergos and Joshua M. HareVasileios Karantalis, Wayne Balkan, Ivonne H. Schulman, Konstantinos E.myocardial remodelingCell-based therapy for prevention and reversal of

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Cell-based therapy for prevention and reversal of myocardial remodelingVasileios Karantalis,1 Wayne Balkan,1 Ivonne H. Schulman,1,2 Konstantinos E. Hatzistergos,1

and Joshua M. Hare1

1Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida;and 2Nephrology-Hypertension Section, Miami Veterans Affairs Healthcare System, Miami, Florida

Submitted 15 March 2012; accepted in final form 21 May 2012

Karantalis V, Balkan W, Schulman IH, Hatzistergos KE, Hare JM. Cell-based therapy for prevention and reversal of myocardial remodeling. Am J PhysiolHeart Circ Physiol 303: H256–H270, 2012. First published May 25, 2012;doi:10.1152/ajpheart.00221.2012.—Although pharmacological and interventionaladvances have reduced the morbidity and mortality of ischemic heart disease, thereis an ongoing need for novel therapeutic strategies that prevent or reverse progres-sive ventricular remodeling following myocardial infarction, the process that formsthe substrate for ventricular failure. The development of cell-based therapy as astrategy to repair or regenerate injured tissue offers extraordinary promise for apowerful anti-remodeling therapy. In this regard, the field of cell therapy has mademajor advancements in the past decade. Accumulating data from preclinical studieshave provided novel insights into stem cell engraftment, differentiation, andinteractions with host cellular elements, as well as the effectiveness of variousmethods of cell delivery and accuracy of diverse imaging modalities to assesstherapeutic efficacy. These findings have in turn guided rationally designed trans-lational clinical investigations. Collectively, there is a growing understanding of theparameters that underlie successful cell-based approaches for improving heartstructure and function in ischemic and other cardiomyopathies.

myocardial infarction; stem cells; mesenchymal stem cells; bone marrow cells;heart failure

THIS ARTICLE is part of a collection on Physiological Basis ofCardiovascular Cell and Gene Therapies. Other articles ap-pearing in this collection, as well as a full archive of all collec-tions, can be found online at http://ajpheart.physiology.org/.

Introduction

A recent update from the American Heart Association (140)reported that in 2008, 2.7% of Americans suffered a myocar-dial infarction (MI), �8 million survived an MI, and anestimated 82.6 million were living with one or more types ofcardiovascular disease, costing a staggering $300 billion thatyear. These statistics underscore the challenges facing ourhealth care system today. While advances in both pharmaco-logical and interventional approaches for revascularizationhave significantly reduced the morbidity and mortality ofischemic heart disease over the past half-century, they do notdirectly reverse the major reason for ventricular failure andelectrical system disturbance, the progressive ventricular re-modeling that follows an MI. Therefore, the need for noveltherapeutic modalities is paramount. In this regard, encourag-ing results from preclinical studies and phase I–III clinicaltrials (Fig. 1) suggest that stem cell therapy provides anti-remodeling effects leading to the restoration of contractilefunction in patients with ischemic cardiomyopathy.

With the discovery of cardiac stem cells (CSCs), the notionthat adult myocardial tissue has endogenous regenerative ca-pability (12) signaled the beginning of a new era in cardiovas-cular medicine. A stem cell is defined by its ability to self-renew and to differentiate into one or more lineages of spe-cialized cell types (151). In addition, stem cells are generallyorganized in niches where their interaction with other cell types(including other stem cells) and the stroma maintains their“stemness” (61, 110, 173). Characteristics of an ideal stem cellfor use in cardiac cell-based therapy are availability, tissueresidence or homing specifically to the injured tissue, ability tomobilize endogenous repair mechanisms that are otherwiseoverwhelmed by the magnitude of damage, and providing asustainable benefit that translates as prevention or reversal ofpathological remodeling and as improvement of left ventricular(LV) function. Previous and ongoing preclinical studies andclinical trials suggest that there are many stem cells that couldplay this role. Determining the most effective stem cell(s) andalso understanding the mechanisms by which they exert theirtherapeutic effects are the focus of current studies (96, 104).Each stem cell type, in theory, exhibits some of the character-istics that contribute to a capacity to exert a therapeuticresponse. As is typical in the evolution of new therapeuticstrategies, the ultimate proof derives from clinical testing, andin this regard, some cell therapeutic strategies have not pro-duced the hypothesized improvements in clinical endpoints(161). Nevertheless, in this early stage of stem cell therapy,both the successes and the failures are informative. This articlewill review the different types of stem cells and recent ad-vances and molecular mechanisms underlying cell-based ther-

Address for reprint requests and other correspondence: J. M. Hare, Biomed-ical Research Bldg., 1501 N.W. 10th Ave., Rm. 824, PO Box 016960 (R125),Miami, FL, 33101 (e-mail: jhare@med.miami.edu).

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apeutic modalities for preventing or reversing myocardial re-modeling.

Pluripotent Stem Cells

Pluripotent stem cells, such as embryonic stem cells (ESCs)that can differentiate into all adult cell types, have fundamentalcharacteristics that could produce cardiac regeneration,namely, the ability to differentiate into cells that resemblespontaneously beating cardiac myocytes and express charac-teristic cardiac myocyte transcription factors (45) as well asinto cells that participate in neovascularization (106). Whentransplanted into infarcted rodent myocardium, ESC-derivedcardiac myocytes engraft and improve cardiac function (111,113). However, their immune-privileged properties have beenquestioned (189), and ethical, legal, and biological (15, 41)issues have hampered the use of ESCs in human trials. Theability to circumvent these problems by reprogramming adultsomatic cells into ESC-like, induced pluripotent stem cells(177) or induced cardiomyocytes (64) potentially provides anattractive alternative to ESCs. These cells have only recentlybeen investigated in clinical trials (71, 119), but the reproduc-ibility, durability, and safety of human cell reprogramming and

genetic engineering strategies remains the subject of intenselaboratory investigation.

Umbilical Cord Blood Stem Cells

Umbilical cord blood contains a wide variety of stem cells,including hematopoietic stem cells (176), mesenchymal stemcells (MSCs) (23), and a population of unrestricted somaticstem cells (83), that can be differentiated both in vitro and invivo into numerous cell types, including cardiomyocytes (83).Although umbilical cord blood stem cells have generatedconflicting results in preclinical studies (75, 83, 101, 114),there are studies (27) showing that Wharton’s jelly-derivedMSCs have a greater endothelial differentiation capacity thanbone marrow-derived MSCs, and they are currently the subjectof the phase-II clinical trial, Intracoronary Human Wharton’sJelly-Derived Mesenchymal Stem Cells (WJ-MSCs) Transferin Patients With Acute Myocardial Infarction (WJ-MSC-AMI;NCT01291329).

Skeletal Myoblasts

Skeletal myoblasts (satellite cells) are a population of qui-escent stem cells located under the basal lamina of muscle

Fig. 1. Ongoing clinical trial activity evaluating cell-based therapy for heart disease. A: topographic representation of ongoing clinical trials currently registeredwith ClinicalTrials.gov employing stem cell therapy for myocardial infarction (map adapted from ClinicalTrials.gov). B: types of delivery systems. IC,intracoronary infusion; IM, intramyocardial injection; IV, intravenous infusion. C: number of patients enrolled in clinical trials of different phases. BMC, bonemarrow-derived stem cells; MSC, mesenchymal stem cells; CSC, cardiac stem cells.

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fibers that proliferate in response to injury to help regeneratemuscular tissue (19). Although they have limited differentia-tion ability, skeletal myoblasts, based on the concept that thesecells would have sufficient plasticity for cardiac myocytedifferentiation, have been investigated as a potential therapeu-tic approach for myocardial regeneration (1, 53, 162). Studiesindicate that skeletal myoblasts are unable to couple electro-mechanically with the endogenous cardiomyocytes, and thisdeficit is likely the basis of the detrimental ventricular tachy-arrhythmias observed in early studies (154, 156). Thus, despitemore than 40 preclinical studies, questions regarding the safetyand efficacy of these cells remain (154, 156), and there isrelatively less enthusiasm for this cell type compared withother alternatives.

Bone Marrow-Derived Stem Cells

There is intense interest in the bone marrow as a source ofcells with capacity for cardiac repair, and bone marrow hasbeen widely tested in mechanistic studies and clinical trialsfor cardiac disease. Bone marrow harbors a wide variety ofstem/precursor cells with potential for cardiac differentia-tion. Some, but not all, studies support the idea that bonemarrow-derived stem/progenitor cells (BMSCs) (20) havethe capacity to differentiate into cardiac myocytes andendothelial cells (123, 124). These characteristics and therelative accessibility of bone marrow have supported thehypothesis that autologous BMSCs and/or its stem/progenitor cell populations could produce phenotypic andclinical recovery in patients with remodeled ventricles.Preclinical studies have demonstrated that whole bone mar-row (8, 65, 70, 118, 123) improves hemodynamic parame-ters and cardiac morphology. Kamihata et al. (70) showedthat whole bone marrow improved myocardial perfusion andreduced infarct size in a swine model. In addition, the newlyformed capillaries, but not the fibroblasts, in the infarct areawere derived from donor BMSCs, supporting the notion thatBMSC therapy produces a proangiogenic rather than afibrosis-inducing microenvironment.

Endothelial progenitor cells and mononuclear cells. In ad-dition to whole bone marrow, numerous studies have beenconducted examining specific constituents of bone marrow.Endothelial progenitor cells (EPCs) share certain phenotypicand functional characteristics with fetal angioblasts (80) andexpress the surface markers CD34, CD133 (5), Flk-1 [vascularendothelial growth factor (VEGF) receptor-2] (128), andAC133 (hematopoietic stem cell marker not expressed onmature endothelial cells) (51). In preclinical studies, EPCspromote neovascularization, leading to the prevention of LVremodeling and to some degree of cardiomyocyte regeneration(147). Although several phase-1 clinical trials have reportedpreliminary feasibility and safety data with EPC therapy afterMI, most of these studies actually investigated bone marrow-derived mononuclear cells (MNCs), not isolated EPCs (150).In the Transplantation of Progenitor Cells and RegenerationEnhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial (91), patients with acute MI received an intracoro-nary infusion of ex vivo expanded bone marrow MNCs orculture-enriched EPCs derived from peripheral blood MNCs.With this strategy, there was sustained improvement in LVfunction, reduction in end-systolic volume, and prevention of

remodeling one year later in both the bone marrow MNCs andculture-enriched circulating EPC treatment groups. Given thepromising findings of the TOPCARE-AMI trial, additionalclinical investigations are underway. Notably, the EnhancedAngiogenic Cell Therapy-Acute Myocardial Infarction Trial(ENACT-AMI) is a phase-II clinical trial that will investigatethe efficacy and safety of autologous EPCs and autologousEPCs transfected with human endothelial nitric oxide synthase(NCT00936819).

While there is substantial evidence for the safety of bonemarrow MNCs from clinical trials, there are inconsistent find-ings as to their efficacy. The TOPCARE-AMI (91) and theBOne marrOw transfer to enhance ST-elevation infarct regen-eration (BOOST) trials (144) recently completed their 5-yearfollow-up. These trials, which together totaled 119 patients,illustrated the long-term safety of this cell-based therapy ap-proach. In TOPCARE-AMI, the improvement in LV ejectionfraction (LVEF) in the treated group was sustained, but resultsfrom BOOST showed that the early (6 mo) improvement inLVEF in the treated group was not sustained at 5 years. Theseinconsistent findings emphasize the importance of examiningin future trials the long-term sustainability of cell-based ther-apy.

Furthermore, the First Mononuclear Cells injected in theUnited States conducted by the Cardiovascular Cell TherapyResearch Network (FOCUS-CCTRN) phase-2 trial evaluatedwhether transendocardial delivery of bone marrow MNCsimproves LV performance and perfusion at 6 mo in patientswith chronic ischemic cardiomyopathy (130). Although therewas no improvement compared with placebo in LV end-systolic volume, maximal oxygen consumption, or myocardialperfusion, exploratory analyses showed significant improve-ment in LVEF and stroke volume. Interestingly, the improve-ment in ejection fraction was associated with higher bonemarrow CD34� and CD133� progenitor cell counts. Theseresults suggest that the cellular composition of the bone mar-row may determine clinical end points, with certain cell pop-ulations providing a greater regenerative benefit.

MSCs for ischemic heart disease. MSCs comprise �0.01%of bone marrow and are operationally defined as plastic-adherent, hematopoietic lineage negative cells of the MNCfraction of the bone marrow (133). MSCs have also beenisolated from virtually every tissue type (33) and are thought toparticipate in niches, regulating the function of hematopoieticcells (26) and other specific lineages (40). Interestingly, MSCsalso differentiate into bone, tendon, cartilage, fat, and muscle,raising the possibility of their use in disorders of organ systemscomprising those tissues (26). While these cells express nu-merous cell surface markers, including CD105, CD73, andCD90 (190), no single cell surface marker indisputably char-acterizes MSCs. Furthermore, MSCs may lose the expressionof certain surface markers or even acquire the expression ofnew ones as they are isolated and expanded in vitro (67).Therefore, MSCs are not a homogenous population of cells(120) and whether MSCs from different tissues are biologicallyequivalent remains to be determined (191).

Multilineage differentiation potential has become one of thedefining characteristics of MSCs (7). Under specific cultureconditions in vitro, these cells can differentiate into osteocytes,chondrocytes, adipocytes, smooth muscle cells, fibroblasts,endothelial cells, (132) and cardiomyocyte-like cells (102).

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Caplan (21) showed that differentiation depends on the cellularmilieu. For example, bone marrow-derived MSCs (BM-MSCs)cultured in the presence of 5-azacytidine differentiate intomultinucleated myotubes that express �-myosin heavy chain,desmin, and �-cardiac actin and also display spontaneousrhythmic calcium fluxes (180). Murine BM-MSCs culturedunder the same conditions started beating spontaneously, con-nected to adjoining cells, and became synchronized after 2 to 3wk (102). Those cells adopted two types of action potentials,sinus node-like and ventricular myocyte-like, and exhibitedcardiomyocyte-specific gene expression (atrial natriuretic pep-tide, �- and �-myosin heavy chain, Nkx2–5, and GATA4)(102). Rat BM-MSCs cocultured with neonatal rat ventric-ular myocytes differentiated into cardiomyocytes that con-tracted, expressed sarco(endo)plasmic reticulum calcium-ATPase 2 and ryanodine receptor 2 and were positive fortroponin T, �-actinin, and desmin (98). Another factor thatmay promote cardiomyocyte differentiation is mechanicalloading (131). Several studies have revealed two mainregulatory pathways of MSCs differentiation, the Wnt (17,37, 44) and the transforming growth factor (TGF)-� path-ways (4, 7), but there is a plethora of other molecules thathave been shown to play a regulatory role, such as epider-mal growth factor, platelet-derived growth factor, and fibro-blast growth factor (108, 165).

Animal studies have established that MSCs are capable ofdifferentiating into cardiomyocytes and/or vascular structuresin both allogeneic (61, 145) and xenotransplantation (166)models, resulting in significant functional improvement andreduction of ischemic scar area. Interestingly, animals sub-jected to allogeneic MSC transplantation did not manifestevidence of rejection (3, 141), consistent with observations byseveral groups that MSCs exhibit immune-privileged proper-ties in vitro and in vivo (56), likely because of the absence ofMHC-II, B-7 costimulatory molecules, and CD40 ligand (170).The lack of costimulatory molecules prevents T-cell responsesand also induces an immunosuppressive local microenviron-ment through the production of prostaglandins and other sol-uble mediators such as nitric oxide, indoleamine 2,3-dioxyge-nase, and heme oxygenase-1 (24, 79, 84, 138, 143). MSCsreduce the respiratory burst that follows neutrophilic responsesby releasing interleukin-6 (136). They also inhibit the differ-entiation of immature monocytes into dendritic cells, hence theantigen presentation to naïve T cells is greatly impaired (66). Inaddition, MSCs release soluble factors, such as hepatocytegrowth factor and TGF-�1 (39) that suppress the proliferationof cytotoxic and helper T cells.

The potential clinical application of MSCs was exploredearly in the developing field of cell-based therapy. Chen et al.randomized 69 patients post-MI to receive intracoronary ad-ministration of either autologous MSCs or placebo. They usedsingle positron emission computer tomography and detected asignificant improvement in LV function and perfusion defect,suggesting that MSC therapy induces regeneration of infarctedmyocardium and protects against LV remodeling (28). Wecompared the therapeutic benefit of intravenous administrationof allogeneic MSCs to placebo in 60 patients after acute MI(60). In addition to establishing the safety of allogeneic MSCdelivery to humans, echocardiography revealed a 6% increasein LVEF at 3 mo for MSC-treated patients. In addition, patientsreceiving MSCs had improved quality of life, better respiratory

function, and a near eradication of ventricular arrhythmias.Recently, Williams et al. (179) reported the results from thefirst eight patients of the Transendocardial Autologous Cells inIschemic Heart Failure Trial (TAC-HFT), in which autologousBMSCs (either culture expanded MSCs or MNCs) were in-jected intramyocardially into patients with chronic ischemiccardiomyopathy. These patients demonstrated improved re-gional myocardial contractility and decreased infarct size.Notably, early improvements in regional function predicted thedegree of reverse remodeling 12 mo following cell therapy.These early investigations have engendered a plethora of on-going trials testing the capacity of MSCs or MSC precursorsfor myocardial regeneration. Importantly, the findings fromthese studies have also indicated that the selection of endpoints, such as direct measures of infarct size and ventricularremodeling, that accurately reflect clinical outcomes couldrepresent more suitable measures of efficacy for cell therapy(161, 179) than LVEF, which most cell therapy trials have usedas the primary end-point marker of efficacy.

As previously mentioned, MSCs have the capacity to beused as an allogeneic cell therapeutic. To test whether alloge-neic MSCs are as safe and effective as autologous MSCs, ourgroup is conducting The Percutaneous Stem Cell Injection DeliveryEffects on Neomyogenesis Pilot Study (The POSEIDON-PilotStudy; NCT01087996), the first direct randomized head-to-head comparison of autologous versus allogeneic MSCs deliv-ered by transendocardial, intramyocardial injection. This studywill help determine whether or not allogeneic MSCs, a cost-effective “off the shelf” cell product, are equally effective as atherapeutic regimen as autologous MSCs and will also definethe relative advantages of the autologous versus allogeneicapproach in various patient populations.

MSCs for nonischemic heart disease. Although the majorityof cardiac cell-based therapy studies have targeted acute MIand ischemic cardiomyopathy, it is important to point out thata significant number of heart failure patients have nonischemiccardiomyopathy. Idiopathic dilated cardiomyopathy (DCM) isa leading cause of heart failure morbidity and mortality andaccounts for �50% of heart transplants (163). The primaryphenotype of DCM is an enlarged, remodeled ventricle withincreased end-diastolic and end-systolic volumes, reducedejection fraction, and impaired contractile and diastolic func-tion. Given that cell-based therapy produces durable and sus-tainable improvements in cardiac function and causes reverseremodeling in ischemic cardiomyopathy, it is attractive tohypothesize the same for patients with nonischemic cardiomy-opathies. If these effects can be clinically established andoptimized, there is enormous potential for improving clini-cal outcomes for the many patients suffering from DCM. Acase report and small clinical study on the safety andfeasibility of cell therapy for DCM (86, 109) were encour-aging and indicate that larger scale randomized trials arewarranted. Accordingly, we have initiated a clinical trial toestablish the safety and efficacy of bone marrow-derivedMSC therapy for patients with DCM. The Percutaneous Stem CellInjection Delivery Effects on Neomyogenesis-Dilated Cardiomy-opathy (POSEIDON-DCM; NCT01392625) study is a random-ized comparison of autologous versus allogeneic MSC therapyemploying percutaneous delivery with a transendocardial cath-eter delivery system.

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Cardiac Stem Cells

The realization that adult myocardial tissue(s) have endog-enous regenerative capability (12) dramatically shifted thelong-held view that the heart is a terminally differentiatedorgan without regenerative capability. It has now becomeevident that there are myocytes in the heart expressing the cellcycle proteins CDC6, Ki67, MCM5, serine 10-phosphorylatedhistone H3 (PH3; Fig. 2B), and aurora B kinase, indicating thatthese cells can replicate (11). The rate of replication of thesemyocytes increases substantially in pathological states (93).Two possibilities could account for the presence of these cells:replicating CSCs (Fig. 2C) evolving into transient amplifyingcells or mature myocytes that have dedifferentiated and reen-tered the cell cycle (14, 43, 85). A landmark study by Beltramiet al. (12) was the first to challenge the dogma that the adultmyocardium lacks regenerative capacity. The authors reporteda population of cardiac Lin� c-kit� cells possessing the prop-erties of CSCs. These cells gave rise to cardiomyocytes,smooth muscle cells, and endothelial cells; indicating theirability to undergo trilineage differentiation, reconstitute myo-cardium, and form new blood vessels and cardiomyocyteswhen injected into an ischemic heart. Accordingly, this studyestablished that the adult mammalian heart does indeed containa compartment of stem cells.

CSCs are a diverse cell population. They are approximatelyone-tenth the size of mature cardiac myocytes and express thestem cell factor receptor c-kit (CD117) (12), stem cell antigen1 (Sca-1; an antigen present in rodents but not mammals)(122), and in some cases the transcription factor Islet-1 (89),which in neonatal hearts marks the second heart field. Islet-1 isalso reported in cardiosphere-derived cells (discussed below)derived from postnatal hearts (112). Hierlihy et al. (62) iden-tified a side population of cells that form colonies in vitro(semisolid media) and differentiate into cardiomyocytes. Inter-estingly, these cells were found to be activated when growth ofthe postnatal murine heart was attenuated, through overexpres-sion of a dominant negative cardiac transcription factor

(MEF2C), and subsequently depleted. These findings weresuggestive of a responsive CSC pool in the adult myocardium.Additionally, Martin et al. (107) detected another side popula-tion of cells that are capable of proliferating and differentiatinginto cardiac and hematopoietic lineages in vitro. These cellswere identified based on their expression of Abcg2, an ATP-binding cassette transporter.

Another source of CSCs may emerge from studying theintegral role of the epicardium in heart development (158),which in lower vertebrates (68, 74) participates in cardiacregeneration. Although several groups have studied the pres-ence of c-kit� cells in the epicardium with variable results(100, 184), there is now mounting evidence for the presence ofepicardial progenitor cells that resemble MSCs (29). FollowingMI, these cells undergo endothelial-to-mesenchymal cell trans-formation (22). The acquisition of a mesenchymal phenotypeand subsequent migration from the subepicardial space into themyocardial wall is followed by proliferation and formation ofmyocardial precursors and vascular cells (22, 38, 100). Fur-thermore, MI triggers the activation of fetal epicardial genes(Tbx18, WT1, and retinaldehyde dehydrogenase type 2) (99).Limana et al. (99) demonstrated in infarcted murine hearts thatepicardial progenitor cells coexpress c-kit and WT1 and/orTbx18, suggesting that these cell populations are epicardialcardiogenic precursors.

The identification of progenitor cells in the epicardium withESC characteristics suggests that signaling factors that modu-late embryonic epicardial cell functions may also contribute tothe activation of adult epicardial progenitors. Several growthfactors that contribute to coronary vessel formation [erythro-poietin, VEGF, fibroblast growth factor (FGF), thymosin �4]have been administered in animal models of MI and heartfailure resulting in enhanced vascularization (2, 90, 139, 171).Smart et al. (155) studied cardiac-specific thymosin �4 knock-down mice and demonstrated that the loss of thymosin �4 mayresult in impaired paracrine signaling to the epicardium, lead-ing to impaired coronary vascular formation. Furthermore, it

Fig. 2. Mechanisms of cardiac regeneration. Mammalian myocyte renewal may result from stem cell differentiation and/or myocyte mitosis. These processes arelikely linked in that CSCs become mature myocytes by becoming transient amplifying cells, a process enhanced by MSCs. A: Masson’s trichrome (Masson’sTri) histological stain obtained from the border zone between infarcted and viable myocardium in the porcine heart. In this image viable new myocytes are shownin red and scarred myocardium in blue. Immunohistochemical analysis for the mitotic marker serine 10 phosphorylated histone H3 (PH3; white nucleus) in Band c-kit (green) in C suggests regeneration of new myocardium from replicating myocytes and adult c-kit� CSCs, respectively. The relative contribution of CSCsor adult dedifferentiation to myocyte entry into the cell cycle is not definitively defined. The spatial and temporal colocalization of c-kit cells and the PH3myocytes in an animal treated with MSCs is suggestive that the mitotic cells represent transient amplifying cells (61, 94).

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has been shown that systemic administration of thymosin �4 inmice after MI results in decreased cardiomyocyte death (159)and reactivation of the embryonic program, as demonstrated bythe epicardial increased expression of VEGF, Flk-1, FGF17,FGF receptor-2, FGF receptor-4, TGF-� and �-catenin (16).

CSCs are likely supported and maintained within cardiactissue in specialized microenvironments termed “stem cellniches” (48, 115). Niches are located in the myocardial inter-stitium where CSCs can maintain their “stemness” by formingconnections with other stem and supporting cells, i.e., maturecardiomyocytes and fibroblasts, through connexins and cad-herins. Niches have been detected throughout the myocardiumand are concentrated at the atria and apex (172), and it is fromwithin these niches that endogenous stem cells proliferate andthen migrate to the injury site after an ischemic incident (122).CSCs and side population cells most likely mediate endoge-nous mechanisms for minor repair and for replacement ofongoing cell turnover within the adult heart. The endogenousrepair appears to be limited to noninfarcted tissue (13) and mayattenuate the progression to heart failure. However, significantcellular injury, as inflicted by an MI, could overwhelm theregenerative ability and contribute to stem cell and nichedepletion or destruction (94).

It has been proposed that cardiospheres mimic cardiacniches (95). Cardiospheres contain a central cluster of c-kit�

cells, layers of differentiating cells expressing myocyte pro-teins and the gap junction protein, connexin 43, and an externallayer of mesenchymal cells. When transplanted into murine-injured hearts, cardiospheres exhibit enhanced engraftment andimproved myocardial function compared with cells grown in amonolayer. This difference may in part be due to the presenceof connexin-43 gap junctions. Connexin 43 plays a differenti-ation-dependent role. In more differentiated cardiomyocytes,connexin 43 promotes cell-cell electrical coupling (72), whereas inless mature cells it promotes proliferation and differentiation(55, 125). Dissociation of cardiospheres into single cells de-creased the expression of adhesion molecules and underminedresistance to oxidative stress, thereby reducing their ability toengraft and their functional benefit (95). On the other hand, Yeat al. (182) isolated and cloned Sca-1�CD45� cardiosphere-derived cells and injected them into post-MI mice hearts. Theyobserved that cloned Sca1�CD45� cells induced angiogenesis,differentiated into endothelial and smooth muscle cells, andimproved cardiac function. Interestingly, the expression of thetranscription factor Islet-1 was threefold higher in theSca1�CD45� cells than in whole cardiospheres. Islet-1 isexpressed in a cell population that gives rise to both myocardialand vascular tissues (89). These studies suggest that cardio-spheres provide a niche-like environment that helps resistoxidative stress and maintain “stemness,” whereas isolation ofcells from cardiospheres promotes their differentiation andlineage commitment. Further studies are needed to elucidatethe mechanisms involved in the balance between resistance tooxidative stress and relevant lineage commitment.

Clinical trials employing CSCs. CSCs can be harvested frompatient cardiac biopsies and expanded ex vivo to generate largenumbers of autologous cells (10), which can then be deliveredback to the patient. Recently published results from the phase-Iclinical trial Cardiac Stem Cell Infusion in Patients WithIschemic CardiOmyopathy (SCIPIO) (18) demonstrated thatintracoronary infusion of autologous c-kit� CSCs is effective

at improving LV systolic function and reducing infarct size inpatients with heart failure after MI. These results are veryencouraging and provide rationale for larger randomized trialsthat will extend these observations to test whether clinicalbenefits derive in patients receiving infusions of these cells.

A phase-I randomized clinical trial of cardiospheres as acell-based therapeutic was also recently completed. The CAr-diosphere-Derived aUtologous stem CElls to reverse ventricU-lar dySfunction (CADUCEUS) trial (103) included 25 patientswho had suffered an MI and who were randomized to receivecardiosphere-derived cells (by intracoronary infusion) or stan-dard care. Magnetic resonance imaging (MRI) analyses 6 moafter treatment with cardiospheres showed a reduction in scarmass and an increase in viable heart mass, regional contractil-ity, and regional systolic wall thickening. In contrast to thestudy of culture-expanded c-kit� CSCs, cardiospheres did notaugment parameters of integrated cardiac performance such asLVEF.

Mechanisms of Action of Cell-Based Therapy

The initial motivation for stem cell research and cell-basedtherapy was the idea that the injection of stem cells into ascarred myocardium would promote regeneration throughtransdifferentiation of the exogenously delivered stem cells, ahypothesis supported by Orlic et al. (123). However, thetotality of ongoing mechanistic and translational studies hashighlighted the fact that the therapeutic process is a multifac-eted, orchestrated process involving multiple mechanisms ofaction.

The in vivo mechanism of action of MSCs is under intenseinvestigation in an effort to shed light on the multifacetednature of cell-based stimulation of cardiac repair (3, 135, 166,181). MSCs engraft and differentiate when transplanted in theheart (61, 135). In this regard, Toma et al. (166) used immu-nofluorescence staining with anti-�-galactosidase to identifyengrafted MSCs (labeled with lacZ) intramyocardially deliv-ered to murine hearts. Engrafted MSCs expressed markers ofmyocardial differentiation as early as 14 days postinjection.Building on these early results, many studies followed inrodent (149) as well as swine models (3, 61, 145, 185). Thestudy by Quevedo et al. (135), using a swine model of ischemiccardiomyopathy, showed that 14% of engrafted MSCs demon-strated evidence of cardiomyocyte differentiation. In addition,there was evidence of cell-to-cell coupling between thesedifferentiated MSCs and host myocytes via connexin-43 gapjunctions. In a swine model of acute MI, a combination of astatin and intramyocardial injections of BM-MSCs improvedcardiomyocyte-differentiation capability by fourfold (181).However, not all studies show in vivo differentiation of MSCs.For example, MSC differentiation was not evident in a caninemodel by Silva and colleagues (152), revealing potential dif-ferences between species and/or study designs.

Despite the evidence for differentiation of engrafted MSCs(69, 105, 135), the collective results from studies of MSCshave called into question the correlation between the frequencyof engraftment and differentiation of transplanted MSCs andthe reported functional recovery early posttransplantation. Forinstance, reports of LV functional improvement within 72 hpostinjection cannot be explained by MSC transdifferentiation(117). Based on these observations, some investigators ques-

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tioned whether differentiation occurs at all, raising the theorythat cell fusion with resident myocytes could explain, at least inpart, cardiac recovery (121). On the other hand, the fact that ofhundreds of millions of cells fewer than 10% remain after 2 wkhas lent credence to the paracrine signaling hypothesis (54),whereby exogenous MSCs secrete factors that induce neovas-cularization and prevent cardiomyocyte apoptosis, thereby re-ducing remodeling and improving cardiac function (80, 147).However, the observation of long-term MSC survival, engraft-ment, and trilineage differentiation and that MSC engraftmentcorrelated with functional recovery in contractility and myo-cardial blood flow in a swine model of chronic ischemiccardiomyopathy (105) indicate that stem cells do provide morethan simply paracrine support for repair. Moreover, otherinvestigators have suggested that it may simply be the sheer

mechanical strengthening of the MI scar that prevents furtherdeterioration in cardiac function (121). It is likely that thecombination of short- and long-term effects of MSCs maintainsthe process of reverse remodeling.

With regard to the paracrine signaling hypothesis, variousstudies indicate that MSCs secrete proangiogenic, antifibrotic,and antiapoptotic factors, such as VEGF, stromal-derived fac-tor-1 (77), angiopoietin 1 (73), insulin-like growth factor 1(57), hepatocyte growth factor, periostin (76), and thymosin b4(63). Amado et al. (3) reported that MSCs express VEGF,which is linked to both neoangiogenesis and stem cell homingand migration, but also provided strong evidence of cell dif-ferentiation.

Perhaps the most important insight into the mechanism ofaction derives from studies of cell-cell interactions. In a study

Fig. 3. MSCs stimulate endogenous cardiomyocyte cell (CM) cycling. A and B: quantification of newly formed myocytes of both host (red bar graph,phospho-H3�) and donor (green bar graph, Y chromosome�) origin 2- and 8-wk postinjection, respectively. MSCs stimulated host cardiomyocytes to amplifyduring the first 2 wk following transendocardial injection. The new CMs were mainly distributed at the ischemic zone (IZ) and border zone (BZ) of the treatedhearts, indicating active regeneration of injured myocardium. By 8 wk, endogenous cycling CMs levels had returned to normal values. C and D: mitotic featuresin endogenous CMs from the BZ of an MSC-treated and cell-conditioned media (CCM)-treated heart, respectively. MLC, myosin light chain; DAPI,4,6-diamidino-2-phenylindole. Values are means � SE (n � 3 hearts, each). *P � 0.05, †P � 0.005 between groups; ‡P � 0.05 between groups. Reproducedwith permission from Hatzistergos et al., Circulation Research, 2010 (61).

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comparing MSC conditioned medium versus MSCs them-selves, Hatzistergos et al. (61) demonstrated in a swine modelof MI that intramyocardial injection of MSCs reduced infarctsize by recruiting endogenous c-kit� CSCs, whereas an injec-tion of concentrated MSC-conditioned media had no effect. Inthis study, histological examination revealed chimeric clusterscomprised of adult cardiomyocytes, transplanted MSCs, andhost c-kit� CSCs that expressed connexin-43-mediated gapjunctions and N-cadherin mechanical connections betweencells. Importantly, MSC treatment enhanced substantially theabundance of host c-kit� CSCs and their cardiomyocyte lin-eage commitment capacity. In addition, MSCs and CSCsappeared to create cell clusters closely resembling stem cellniches (Fig. 3). The latter underscores the emerging conceptthat MSCs may act both as progenitors for certain cell lineagesand, through their participation in niches, as supporting/regu-latory cells for other lineages (94). All of the aforementionedmechanistic insights (Fig. 4) allow us to generate a novelhypothesis that cell therapy reconstitutes endogenous stem cellniches—by way of transdifferentiation and paracrine signal-ing—and in that manner facilitate cardiac self-healing.

Timing of Delivery

It is recognized that practical issues such as timing, deliverymethod, and dosing could contribute substantially to the out-come of clinical investigation. In the setting of acute MI, celltherapy seems to have a specific time frame of therapeuticopportunity, a period after MI when the myocardium is more“ripe” for cell therapy (6, 42). In this regard, two clinical trialsare investigating the optimal timing of cell delivery of bonemarrow MNCs with the intent of resolving the questionsregarding their therapeutic potential. The Transplantation inMyocardial Infarction Evaluation (TIME) study is a phase-IItrial developed by the CCTRN to test the efficacy, safety, andmost appropriate timing of bone marrow MNCs in patientsafter acute MI (169). This trial is comparing the effects ofintracoronary delivery of MNCs at 3 and 7 days post-MI inpatients with ST-segment elevation, whereas the recently pub-

lished LateTIME trial tested whether delaying MNC deliveryfor 2 to 3 wk following MI, and primary percutaneous coronaryintervention improves global and regional LV function (59,168). In LateTIME, there were no significant changes betweenbaseline and 6-mo measures in the MNC group compared withplacebo in LVEF, wall motion in the infarct zone, and wallmotion in the border zone, as measured by cardiac MRI. Theseresults suggest that the timing of cell therapy at 2 to 3 wkpost-MI may exceed the therapeutic window.

Insights on the most appropriate timing can be gleaned frompreclinical studies. For instance, Zang et al. (188) attempted todetermine the timing and frequency of cell injections necessaryfor optimal therapeutic efficacy. They examined the relation-ship between frequency of injection and therapeutic potentialby injecting bone marrow cells into murine ischemic hearts atdays 3, 7, or 14 post-MI (monotherapy), at days 3 and 7 (dualtherapy), and at days 3, 7, and 14 (triple therapy). Injectionsolely at day 3 reduced infarct size and improved LV function.However, multiple injections of bone marrow cells had noadditive effect, and delaying cell therapy post-MI resulted inno functional benefit. Moreover, a study by Urbanek et al.(172) showed that endogenous CSCs proliferate immediatelyafter MI, but in the chronic phase, their numbers fall and theremaining CSCs have less regenerative potential. This notion ischallenged by the preliminary results of the TAC-HFT clinicaltrial (179) where functional improvement was achieved even ata very late stage post-MI, when heart failure was well estab-lished.

Delivery Methods

While there is general agreement that stem cells are apromising therapeutic regimen post-MI, determining the mostappropriate stem cell delivery method is still a matter ofvigorous debate. To date many techniques have been de-scribed, including intravenous (9), transarterial (175), intra-coronary (160), intramyocardial—either transepicardial (129)or catheter-based transendocardial (153)—and transvenous in-jection into coronary veins (164). The least invasive, trans-

Fig. 4. Mechanisms underlying cardiac re-generation due to cell-based therapy. Theimprovement in myocardial function andventricular geometry after transplantation ofstem results from multiple coordinated ac-tions of cells used as a therapeutic. Success-ful cell-base therapy, as observed as a resultof MSC and CSC therapy, likely arises fromthe actions of both administered cells andhost cellular elements. Notably, MSCs bothhave the capacity for trilineage differentia-tion, as well as stimulating the recruitment,survival, and differentiation of host CSCs.This action of MSCs results from both se-cretion of cytokines and growth factors [vas-cular endothelial growth factor (VEGF),stromal-derived factor 1 (SDF1), insulin-growth factor 1 (IGF1), angiopoietin 1] andantifibrotic mediators that together promoteneovascularization and reduce fibrosis. To-gether these actions and the recruitment ofendogenous CSCs could represent the recon-stitution of stem cell niches in the myocar-dium.

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venous, has the disadvantage that cells may be trapped in thepulmonary circulation (9) before they even reach the systemiccirculation. Thus far, the most frequently used technique inclinical trials is the percutaneous coronary delivery of cells.The cells are injected via an over-the-wire balloon catheter intothe vessel supplying the ischemic territory. This techniquerequires a transient ischemic period through the inflation of theballoon to give the cells the chance to be distributed and notwashed out, although Tossios et al. (167) proposed that theocclusion is unnecessary.

Intramyocardial delivery of cells is a technique that hasgained momentum in the clinical setting (Fig. 1) (3, 179). Theadvantage of this method lies in the fact that unlike theintracoronary approach, which requires transmigration of the endo-thelial barrier, cells that undergo intramyocardial injection arelargely found in the interstitial space. Conversely, the maindisadvantage is that larger scarred areas require multiple injec-tions. The addition of electromechanical mapping will renderthis approach the most accurate on tracking the ischemic areas(156). Determining the most suitable method and the mostappropriate route of cell delivery will likely depend on theclinical setting and the cell type and no consensus has beenreached.

The common issues surrounding every cardiac deliverymethod employed to date are the reduction of inflammation,stimulation of neovascularization, and improvement in cellengraftment, proliferation, and survival rates (174). To addressthese issues, new experimental strategies are emerging usingcardiac tissue engineering. The general strategy involves acombination of cells and biomaterials (hydrogel or three-dimensional scaffolds) (148). This approach promotes greatercell retention (higher viscosity than saline-based suspension)and survival (antiapoptotic biomaterials) (31, 137). A varietyof biomaterials have been investigated, including fibrin (142,186), collagen (34), Matrigel (82), self-assembling peptides(35), chitosan (183), and alginate (92) in combination withskeletal myoblasts (30), endothelial cells (36), bone marrowMNCs (186), MSCs (187), ESCs (81), and neonatal cardiomy-ocytes (36). Although there are obvious advantages to thisstrategy, there are also some disadvantages. The biomaterialslack flexibility and thus cannot successfully mimic the myo-cardial mechanical microenvironment (50). In addition, theydegrade relatively quickly, and, more importantly, the en-grafted cells create isolated “islands” with no direct cell-cellinteraction with the surrounding tissue (49).

Optimal Dosage of Cell Therapy

Another issue defining an effective therapy is the appropriatequantity of cells transplanted. Instinctively, in stem cell therapyit may be assumed that the more cells transplanted the largertheir beneficial impact would be. Two studies that addressedcell dosage reported interesting results that introduce the notionof the threshold effect. Hamamoto and colleagues (58) injectedsheep with one of four different dosages (25, 75, 225, and 450million allogeneic STRO-3-positive MSCs) or cell media, 1 hpost-induced MI. When compared with control, low-dose (25and 75 million) cell treatment significantly attenuated infarctexpansion and increases in LV end-diastolic volume and LVend-systolic volume. LVEF was improved at all cell doses. Onthe other hand, Schuleri et al. (146) reported a significant

reduction in infarct size in high-dose (200 million) autologousMSC-treated swine compared with low-dose (20 million) au-tologous MSC-treated animals. The regional contractility, asassessed by tagged MRI-derived peak Eulerian circumferentialshortening, was improved in both groups, although the con-tractility of the infarct zone was improved only in the higherdose-treated animals (Fig. 5).

Emerging Trends

Although cell therapy has progressed substantially since thelandmark trials at the beginning of the 21st century, manyquestions remain unanswered regarding the best cell type, thesource of cells, the route of delivery, the timing of the inter-vention, and the number of the cells needed. Studies havesuggested that cells harvested from patients do not show thesame benefit as those from healthy individuals (52), highlight-ing the need for a better understanding of the mechanismsleading to stem cell function and dysfunction. There is aplethora of preclinical studies that suggest strategies to im-

Fig. 5. Dose responsiveness of cardiac functional recovery to intramyocardialMSCs. Plots depict peak circumferential shortening (peak Ecc) in the infarct,border, and remote zones. Peak negative Ecc values represent myocardialshortening and increased contractility, whereas increasingly positive valuesindicate myocardial dysfunction. Ecc improves after cell therapy in both low-and high-dose cell groups in border zones. In contrast, Ecc improves in infarctzones only in the high- and not the low-dose MSC group, consistent with adose-response effect to MSC therapy in that zone. *P � 0.05 vs. placebo;†P � 0.05 week 12 vs. week 24. Reproduced with permission from Schuleri etal, European Heart Journal, 2009 (146).

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prove homing and engraftment capacity of stem cells, whichwill potentially translate into better clinical results (71, 134,157). Two potentially exciting possibilities are the combiningof different stem cells or the combination of cell and genetherapy. Recently, microRNAs have assumed a role as poten-tial regulators of cardiovascular biology, vascular growth, andstem cell differentiation and may be attractive targets to opti-mize cell-based therapies (25).

A major issue with cell-based therapy is cell survival, andthe recipient environment seems to play a major role. HumanMSCs were injected into rat infarcted or healthy myocardiumand after 28 days; 90% of human MSCs were still found in thehealthy myocardium, whereas only 18% of those injected inthe infarcted zone were detectable (88). This observationsupports the idea that ischemia creates an unfavorable envi-ronment, likely because of locally expressed proinflammatorycytokines inducing cell apoptosis (47). Preconditioning, byincubation of stem cells with prosurvival factors (e.g., stromalderived factor 1a) (126), increased cell survival by 20% andreduced the number of dying cells in the peri-infarct region by33%. A more complicated approach is transfection of stemcells with prosurvival or antiapoptotic (i.e., Bcl-2) genes (97).Another focus of genetic modification of stem cells is theserine-threonine kinases, Akt, and its downstream targetPim-1, both of which appear to play a crucial prosurvivalsignaling role in the myocardium (32, 116). Normally, theexpression of Pim-1 is low in mature human and murinemyocardium. MI and its sequelae are accompanied by a reac-tivation of Akt and Pim-1 signaling, but this overexpressionafter injury is apparently insufficient to (completely) reversethe damage (116). Fischer et al. (46) modified CSCs to stablyoverexpress Pim-1 and injected them into murine infarctedmyocardium. They reported greater levels of cellular engraft-ment, survival, and functional improvement for Pim-1-overex-pressing cells relative to control 32 wk postdelivery.

Preconditioning the recipient environment represents an-other therapeutic approach. Activation of the Akt system re-duced post-MI myocardial apoptosis by �41% and infarct sizeby 7% in a rodent model (78). Alternatively, inhibition of localinflammation may increase cell survival. Patel et al. (127) usedan adenosine agonist at the time of coronary reperfusion in acanine MI model and reported a 16% reduction of infarct size.Moreover, simultaneous delivery of MSCs and VEGF to ische-mic myocardium increased MSC survival by almost three-fold (134).

Laflamme et al. (87) coinjected a “cocktail” of six differentagents together with cardiomyocytes derived from ESCs in amurine heart post-MI. Each agent was chosen based on adifferent beneficial function. Z-Val-Ala-Asp-fluoromethylk-etone was used to inhibit caspase-induced apoptosis, cyclo-sporine and Bcl-XL peptide to block different mitochondrialdeath pathways, pinacildil to open ATP dependent potassiumchannels, Matrigel to prevent anoikis, and insulin growthfactor-1 to promote cell proliferation. This combinatorial ap-proach resulted in a 2.5-fold increase in LV wall thickeningand suggests that a combination of cell types and/or factors willprove the most efficacious in eliciting a favorable remodelingresponse. Evidence to this effect is found in a preliminaryreport in a porcine MI model showing that the combination ofMSCs and CSCs is more effective at reverse remodeling thaneither cell type alone (178).

Conclusion

In summary, the use of cell-based therapy in acute MI andchronic ischemic cardiomyopathy is rapidly emerging as atherapeutic approach with enormous clinical potential. Thiscell-based approach also holds promise for the treatment ofnonischemic DCM. The next phase of work will likely focusnot only on determining the best cell type(s) to use but, moreimportantly, the mechanisms by which these cells interact withhost cells and elicit their therapeutic effects. As mechanisticunderstanding evolves, there is the growing opportunity toenhance the production and utilization of novel formulations ofcell-based therapeutics.

GRANTS

J. M. Hare is supported by National Heart, Lung, and Blood Institute GrantsRO1-HL-094849, P20-HL-101443, RO1-HL-084275, RO1-HL-107110, andRO1-HL-110737.

DISCLOSURES

J. M. Hare and K. E. Hatzistergos are listed on a patent for cardiaccell-based therapy. J. M. Hare is a consultant to Kardia and receives researchsupport from Biocardia.

AUTHOR CONTRIBUTIONS

V.K. prepared figures; V.K. drafted manuscript; V.K., W.B., I.H.S., K.H.,and J.M.H. edited and revised manuscript; V.K., W.B., I.H.S., K.H., andJ.M.H. approved final version of manuscript.

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