Cells For Cardiac Repair Research Articles

Increased Potency of Cardiac Stem Cells Compared with Bone Marrow Mesenchymal Stem Cells in Cardiac Repair

Whereas cardiac-derived c-kit(+) stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p < .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p < .05). Whereas 1 × 10(6) MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit(+)CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.

Stem Cells in Cardiac Repair – Recent Developments and Future Directions

Myocardial infarction (MI) is the leading cause of death among people in the industrialised world and will, according to the World Health Organization (WHO), become the leading cause of death in the world in 2020. For the treatment of patients with MIs and ischaemic cardiomyopathies, remarkable medical advances have been made during the second half of the 20th Century that have increased patient survival. As a consequence, patients with heart disease are living longer and the incidence of congestive heart failure in patients is significantly increasing. New treatments for patients with acute MI and ischaemic cardiomyopathies are needed. In this regard, the next major advance in the treatment of patients with cardiac disease promises to be stem cells and stem cell products. Currently, basic research scientists and clinicians worldwide are investigating human embryonic stem cells, skeletal stem cells (myoblasts), adult bone marrow stem cells, cardiac stem cells and human umbilical cord stem cells for the treatment of patients with MIs and ischaemic cardiomyopathies. This review highlights the recent developments and the future directions of each of these stem cells in the treatment of patients with heart disease.

Origin and Selection of Stem Cells for Cardiac Repair after Myocardial Infarction

Despite state-of-the-art methods for the early diagnosis and treatment, heart failure resulting from myocardial infarction (MI) continues to be a major cause of morbidity and mortality worldwide. Most of the existing treatment modalities against heart failure are symptom-based, short-term and do not prolong survival. Stem cell-based therapy is promising strategy to lead to cardiac repair after MI. Over the last decade, stem cells with diverse origin, identity, and plasticity have been utilized for the regeneration and repair of damaged myocardium after MI, both in animal models and humans. The major challenges and dilemmas in stem cell therapy after MI included- ethical concerns and alloreactivity (with embryonic stem cells), malignant transformation and vector contamination (with inducible progenitor cells), coronary restenosis (with mobilization of bone marrow stem cells), and cardiac arrhythmias and structural heterogeneity due to non-coupling of cardiac and non-cardiac skeletal cells (with skeletal myoblasts). Therefore, as much as the progress made in the field of cardiac regenerative therapy, questions have been asked on what constitutes the most appropriate source for the stem cells. In particular, the identity, characteristics and ability of the stem cells to retain their fate while being propagated ex vivo have invited a passionate discussion among cell-biologists, geneticists and clinicians. This review summarizes the diverse origin of the stem cells and discusses recent advances made for the identification, selection and propagation of stem cells for the regeneration or repair of damaged myocardium after MI.

Abstract 17476: Transplantation of an Antigenically-Defined Subpopulation of Bone Marrow Mesenchymal Stem Cells Results in Superior Cardiac Repair After a Reperfused Myocardial Infarction

Although bone marrow mesenchymal stem cells (MSCs) have been used quite extensively for cardiac repair, the outcomes have been highly variable. We investigated whether antigenically-defined subpopulations of MSCs would promote superior repair after myocardial infarction (MI). Unfractionated MSCs were obtained from the adherent fraction of bone marrow cells from C57BL/6 mice using expansion culture, and subpopulations were obtained using two-step FACS isolation. Our in vitro studies identified a Sca-1+/CD45-/c-kit-/Thy1+/CD105- MSC population (CD105- MSCs) that exhibited greater mRNA expression of angiogenic molecules (VEGF, HGF), SDF-1, and reduced expression of deleterious molecules, including TNF-a (Figure). The CD105- MSCs also exhibited greater propensity toward cardiac differentiation. The efficacy of these cells for cardiac repair in vivo was tested in a mouse model of reperfused MI. Wild-type (C57BL/6) mice underwent a 30-min coronary occlusion followed by reperfusion, and 48 h later received intramyocardial injection of vehicle (Vehicle, n=8), unfractionated MSCs (MSCs, n=8), or CD105- MSCs (CD105- MSCs, n=6). Echocardiography was performed 4 d prior to coronary occlusion/reperfusion (BSL1) and at 48 h (BSL2) and 35 d after cell injection. Mice were sacrificed at 35 d. LV ejection fraction (EF) was significantly and similarly reduced in all groups at 48 h after MI (Figure). At 35 d after MI, mice injected with CD105- MSCs exhibited greater EF (Figure) and smaller LV end-diastolic volume compared with vehicle-treated and unfractionated MSC-treated mice. We conclude that compared with unfractionated MSCs, intramyocardial transplantation of CD105- MSCs after a reperfused MI results in improved cardiac repair. The use of this MSC subpopulation may potentially improve the outcomes of cell therapy in humans.

Use of human embryonic stem cell derived‐mesenchymal cells for cardiac repair

Human mesenchymal stem cells (hMSC) have proven beneficial in the repair and preservation of infarcted myocardium. Unfortunately, MSCs represent a small portion of the bone marrow and require ex vivo expansion. To further advance the clinical usefulness of cellular cardiomyoplasty, derivation of "MSC-like" cells that can be made available "off-the-shelf" are desirable. Recently, human embryonic stem cell-derived mesenchymal cells (hESC-MC) were described. We investigated the efficacy of hESC-MC for cardiac repair after myocardial infarction (MI) compared to hMSC. Because of increased efficacy of cell delivery, cells were embedded into collagen patches and delivered to infarcted myocardium. Culture of hMSC and hESC-MCs in collagen patches did not induce differentiation or significant loss in viability. Transplantation of hMSC and hES-MC patches onto infarcted myocardium of athymic nude rats prevented adverse changes in infarct wall thickness and fractional area change compared to a non-viable patch control. Hemodynamic assessment showed that hMSCs and hES-MC patch application improved end diastolic pressure equivalently. There were no changes in systolic function. hES-MC and hMSC construct application enhanced neovessel formation compared to a non-viable control, and each cell type had similar efficacy in stimulating endothelial cell growth in vitro. In summary, the use of hES-MC provides similar efficacy for cellular cardiomyoplasty as compared to hMSC and may be considered a suitable alternative for cell therapy.

Stem cells for cardiac repair in acute myocardial infarction

Despite recent advances in medical therapy, reperfusion strategies, implantable cardioverter-defibrillators and cardiac assist devices, ischemic heart disease is a frequent cause of morbidity and mortality worldwide. Cell therapy has been introduced as a new treatment modality to regenerate lost cardiomyocytes. At present, several cell types seem to improve left ventricular function in animal models as well as in humans, but evidence for true generation of new myocardium is confined to the experimental models. In the clinical perspective, myocardial regeneration has been replaced by myocardial repair, as other mechanisms seem to be involved. Clinical studies on adult stem cells suggest, at best, moderate beneficial effects on surrogate end points, but some applications may qualify for evaluation in larger trials. Complete regeneration of the myocardium by cell therapy after a large myocardial infarction is still visionary, but pluripotent stem cells and tissue engineering are important tools to solve the puzzle.

Shedding New Light on the Mechanism Underlying Stem Cell Therapy for the Heart

It is widely accepted that the adult mammalian heart is a terminally differentiated organ with little capacity to regenerate after damage, such as that caused by a myocardial infarction (MI). Nevertheless, mounting evidence suggests that mature cardiomyocytes do slowly turn over (up to 1% per year).1,2 In addition, there are many claims that the heart contains cell populations expressing stem cell markers that could in principle contribute to repair.3,4 However, whether proliferating cardiomyocytes or endogenous stem or progenitor cells actually contribute to cardiac repair after injury has remained unclear – until now. In a study recently published in Cell Stem Cell,5 Lee and colleagues used a clever lineage-tracing approach in mice1 to identify two potential sources of new cardiomyocytes in the adult heart: those arising from the division of existing cardiomyocytes and those formed by differentiation of the endogenous progenitors. Using their transgenic mouse model, they were able to distinguish these two sources of cardiomyocytes. More strikingly, the authors show that some stem cells currently being tested for the ability to improve heart function in cell transplantation trials can enhance the differentiation of endogenous progenitors, whereas others cannot. The study provides new insight into how cell therapy for the heart might work and suggests ways in which optimal cell types for therapy might be chosen – as well as how the controversial outcomes of many clinical trials might be resolved.

Vascular Gene Transfer of SDF-1 Promotes Endothelial Progenitor Cell Engraftment and Enhances Angiogenesis in Ischemic Muscle

Gene therapy approaches to enhance endothelial progenitor cell (EPC) homing may augment cell engraftment to ischemic tissue and lead to a greater therapeutic response. Therefore, we assessed the effects of ultrasound-mediated (UM) transfection of the chemokine stromal cell-derived factor-1 (SDF-1) on homing and engraftment of intravenously administered EPCs and the subsequent angiogenic response in chronically ischemic skeletal muscle. Bone marrow-derived EPCs were isolated from donor Fisher 344 rats, cultured and labeled in preparation for injection into recipient animals via a jugular vein. Using a model of chronic hindlimb ischemia in rats, we demonstrated that UM destruction of intravenous carrier microbubbles loaded with SDF-1 plasmid DNA resulted in targeted transfection of the vascular endothelium within ischemic muscle and greater local engraftment of EPCs. The combination of SDF-1gene therapy and EPCs lead to the greatest increase in tissue perfusion and microvascular density within ischemic muscle, compared to no treatment or either monotherapy alone. Our results demonstrate that UM transfection of SDF-1 improves EPC targeting to chronically ischemic tissue, enhancing vascular engraftment and leading to a more robust neovascularization response.

Close Encounters of the Third Kind

Following vascular injury, endothelial cells become activated in the attempt to repave the damaged luminal surface. In addition, a physical interaction is established not only among the denuded subendothelial matrix, activated platelets, and circulating inflammatory cells but also with the progenitor cells (PCs).1 Endothelial survival, proliferation, and migration, necessary for re-coverage of exposed lamina, are aided by CD34+ PCs that express the vascular endothelial growth factor (VEGF) receptor-2/kinase-insert domain receptor (KDR). However, whether these cells enter the peripheral circulation as a predefined population or acquire their final antigenic phenotype on homing to the peripheral vasculature remains a matter of debate. See accompanying article on page 408 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , de Boer et al propose that human CD34+/KDR+ cells are generated from circulating CD34+ cells after immobilization on activated platelets.2 By using an ex vivo flow model, the authors show that activated platelets favor the homing of CD34+ cells to sites of vascular injury and that, on cell immobilization, KDR is rapidly translocated from an endosomal compartment to the cell surface. Presumably, PCs shed afterward to “carry the message” into the circulation. It is noteworthy that de Boer et al also report an increased coexpression of KDR on CD34+ cells in type-2 diabetes, which was reduced by aspirin treatment. The authors conclude that their data might have implications for the identification of patients with subclinical vascular injury, on the basis of the hypothesis that activated/injured endothelium provides more opportunity …

Update cardiac stem cell therapy

Chronic ischemic heart disease remains one of the most important causes of morbidity and mortality worldwide. Although revascularisation procedures and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available to prevent or even reverse this process. Chronic coronary artery disease and heart failure impair quality of life and are associated with subsequent worsening of left ventricular function. In the recent past experimental and clinical studies have demonstrated the capacity of bone marrow stem cells in cardiac repair and regeneration of compromised heart muscle. Several clinical trials showed the safety and efficacy of autologous bone marrow stem cell transplantation in the patients with acute myocardial infarction or chronic ischemic heart disease. Today the therapeutic strategy of cell administration during cardiac surgery or coronary artery intervention is entering the clinical practice. Biological as well as methodological backgrounds, indications and clinical results of cardiac stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease are reviewed.

Stem Cells in Heart Failure

Stem Cells in Heart Failure

Stem Cells for Cardiac Repair: Status, Mechanisms, and New Strategies

Faced with the end stage of heart disease, the current treatments only slow worsening of heart failure. Stem cells have the potential of self-renewal and differentiation. It is expected to replace and repair damaged myocardium. But many clinical trials have shown that the stem cell therapy of heart failure is modest or not effective. The possible causes for the limited effects of stem cell in curing heart failure are the stem cells which have been transplanted into the ischemic heart muscle may suffer low survival rate, affected by inflammatory molecules, proapoptotic factor, and lack of nutrients and oxygen, and then the stem cells which home and have been completely transplanted to the site of myocardial infarction become very small. Therefore, through preconditioning of stem cells and appropriate choice of genes for mesenchymal stem cell modification to improve the survival rate of stem cells, ability in homing and promoting angiogenesis may become the newly effective strategies for the application of stem cells therapy in heart failure.

Granulocyte Colony Stimulating Factor, Peripheral Blood Stem Cells and Bone Marrow Stem Cells for Cardiac Repair After Myocardial Infarction

Granulocyte Colony Stimulating Factor, Peripheral Blood Stem Cells and Bone Marrow Stem Cells for Cardiac Repair After Myocardial Infarction

Stem Cells in Cardiac Repair

Myocardial infarction is the leading cause of death among people in industrialized nations. Although the heart has some ability to regenerate after infarction, myocardial restoration is inadequate. Consequently, investigators are currently exploring the use of human embryonic stem cells (hESCs), skeletal myoblasts and adult bone marrow stem cells to limit infarct size. hESCs are pluripotent cells that can regenerate myocardium in infarcted hearts, attenuate heart remodeling and contribute to left ventricle (LV) systolic force development. Since hESCs can form heart teratomas, investigators are differentiating hESCs toward cardiac progenitor cells prior to transplantation into hearts. Large quantities of hESCs cardiac progenitor cells, however, must be generated, immune rejection must be prevented and grafts must survive over the long term to significantly improve myocardial performance. Transplanted autologous skeletal myoblasts can survive in infarcted myocardium in small numbers, proliferate, differentiate into skeletal myofibers and increase the LV ejection fraction. These cells, however, do not form electromechanical connections with host cardiomyocytes. Consequently, electrical re-entry can occur and cause cardiac arrhythmias. Autologous bone marrow mononuclear cells contain hematopoietic and mesenchymal stem cells. In several meta-analyses, patients with coronary disease who received autologous bone marrow cells by intracoronary injection show significant 3.7% (range: 1.9-5.4%) increases in LV ejection fraction, decreases in LV end-systolic volume of -4.8 ml (range: -1.4 to -8.2 ml) and reductions in infarct size of 5.5% (-1.9 to -9.1%), without experiencing arrhythmias. Bone marrow cells appear to release biologically active factors that limit myocardial damage. Unfortunately, bone marrow cells from patients with chronic diseases propagate poorly and can die prematurely. Substantial challenges must be addressed and resolved to advance the use of stem cells in cardiac repair including identifying the optimal stem cell(s) that permit transplantation without requirements for host immune suppression; timing of stem cell transplantation that maximizes chemoattraction of stem cells to infarcts; and determining the optimal technique for injecting stem cells for cardiac repair. Techniques must be developed to enhance survival and propagation of stem cells in the myocardium. These studies will require close cooperation and interaction of scientists and clinicians. Cell-based cardiac repair in the 21st century will offer new hope for millions of patients worldwide with myocardial infarctions who, otherwise, would suffer from the relentless progression of heart disease to heart failure and death.

Cell Separation System for Fully Automated Clinical Scale Separation of CD133+ Cells From Bone Marrow Aspirates.

AbstractAbstract 1188An increasing number of clinical trials are enrolling patients in studies designed to examine the safety and efficacy of autologous stem cells for cardiac repair. Recent reports suggest that patients receiving CD133+ bone marrow cells after myocardial infarction, or as a treatment for ischemic cardiomyopathy, may benefit from an increase in global left ventricular function. Today the clinical scale enrichment of CD133+ cells has to be performed as a complex procedure involving numerous manual handling steps as well as a semi-automated magnetic separation process.We have developed a fully automated clinical scale process to purify CD133+ cells out of human bone marrow aspirates. The whole process was performed in a closed system, containing appropriate adaptors and tubing material, suitable for sterile connection of the bone marrow sample and required solutions, respectively.For the whole separation process, the total processing time was reduced from about 4.5 h (previous process) to 2.5 h. In this context, erythrocyte reduction, generation of autologous plasma, labeling time as well as the conditions for immunomagnetic separation of the CD133+ cells and the automatic monitoring of the whole process by a newly developed camera were optimized.To determine the reproducibility and stability of the process, CD133+ cells were separated from bone marrow aspirates with an initial volume of about 60 mL (n=10). The intitial frequency of CD133+ cells amounted to 0.34% (range: 0.11% to 0.66%) and the number of isolated CD133+ cells was 7.9×105 (range: 3.7×105 to 1.9×106). The yield was 47% (range: 23.9% to 50.9%) and the average viability of the separated CD133+ cells achieved 90% (range: 69.9% to 96.9%).The separation process typically achieved a >3.0 log depletion of CD133 negative cells, i.e. 99.9% of CD133 negative cells were removed. The log depletion of different cell types were: 4.0 for CD3+ cells (i.e. 99.99% removal), 3.1 for CD19+ cells, 3.4 for CD56+ cells, 3.2 for CD14+ cells, and 3.7 for CD15+ cells (n=3, respectively).After separation the CD133+ cells were automatically resuspended in 6 mL of clinical grade isotonic NaCl solution. For storage or transport of the cells, the NaCl solution could be automatically supplemented with 10% autologous plasma, generated out of the bone marrow sample during the separation process.The described cell separation system provides a safe and easy way to purify CD133+ cells from bone marrow aspirates within 2.5 h without any intermediate manual steps. The cell preparation in a closed sterile system facilitates a fast and robust enrichment of CD133+ cells. After separation the CD133+ cells are available in small volume and can be formulated for further use e.g. according to requirements for use in regenerative medicine. Disclosures:Essl:Miltenyi Biotec GmbH: Employment. Stuth:Miltenyi Biotec GmbH: Employment. Huppert:Miltenyi Biotec GmbH: Employment. Balshüsemann:Miltenyi Biotec GmbH: Employment. Bauer:Miltenyi Biotec GmbH: Employment. Miltenyi:Miltenyi Biotec GmbH: Employment.

O22. Cardiovascular derivatives of embryonic stem cells in cardiac repair and drug discovery

Derivation of heart and vascular endothelial cells from human pluripotent stem cells (embryonic stem cells or HESCs and induced pluripotency stem cells or hiPS cells) is an area of growing interest both as a route to cell therapy for the heart and as a platform for drug discovery and toxicity. Understanding the underlying developmental mechanisms that control differentiation of pluripotent cells to cardiac progenitors and their derivatives and mimicking these in defined culture conditions in vitro is now essential for moving the field forward. Culture conditions have now been sufficiently refined that cardiomyocyte and vascular differentiation is a fairly efficient and reproducible process. Genetically marked HESCs have been produced in which expression of the green fluorescent protein marker is expressed ubiquitously or driven by specific lineage markers. We have used these tagged lines to trace cardiomyocytes following transplantation into a mouse heart after myocardial infarction and select the progenitors of cardiomyocytes, endothelial cells and smooth muscle cells. Long term survival of the cells and integration into the host heart has been observed and early improvements in cardiac function but these are not sustained. Cardiac repair using stem cell derived cardiomyocytes will likely require more than efficient cardiomyocytes production. More immediate applications of hESC- and hiPSC derived cardiomyocytes and vascular endothelial cells in drug discovery and disease are now close to implementation. Results of these studies, in particular drug responses of hESC-derived cardiomyocytes and an hiPSC model for vascular disease in which Thalidomide has a therapeutic effect, will be shown.

The management of enthusiasm: Motives and expectations in cardiovascular medicine

Debates about appropriate action in medicine often turn on finding the right emotional orientation to new developments. In this article enthusiasm emerges as a key term in a professional 'vocabulary of motive' around innovation, complicating current sociological interest in expectations. The negative associations that adhere to this word among clinical researchers indicate awareness with the difficulty of managing hype and public hopes, but analysis of its use by cardiologists over the past two decades also reveals tension around more specific professional dangers, including 'credulity' and inappropriate activism. An emphasis on clinical trials offers one resolution, but additional narrative strategies can be identified when discussing when to start such trials here illustrated for stem cells for cardiac repair. In particular, while some suggest delaying trials until there is good knowledge of mechanism gained in the laboratory, others support early clinical research through gestures of therapeutic and epistemic modesty.

Aesthetic cardiology: adipose-derived stem cells for myocardial repair.

Stem cell biology has increasingly gained scientific and public interest in recent years. In particular, the use of stem cells for treatment of heart disease has been strongly pursued within the scientific and medical communities. Significant effort has gone into the use of adult tissue-derived stem cells for cardiac repair including bone marrow, blood, and cardiac-derived cell populations. Significant interest in this area has been balanced by the difficulties of understanding stem cells, cardiac injury, and the amalgamation of these areas of investigation in translational medicine. Recent studies have emerged on adipose-derived stem cells which show the potential for cardiac lineage development in vitro and may have application in cell-mediated in vivo therapy for the diseased heart. This review provides a summary of current findings within the field of adipose-derived stem cell biology regarding their cardiac differentiation potential.

Challenges in Using Stem Cells for Cardiac Repair

Of the many diseases discussed in the context of stem cell therapy, those concerning the heart account for almost one-third of the publications in the field. However, the long-term clinical outcomes have been disappointing, in part because of preclinical studies failing to optimize the timing, number, type, and method of cell delivery and to account for shape changes that the heart undergoes during failure. In situations in which cardiomyocytes have been used in cell therapy, their alignment and integration with host tissue have not been realized. Here we review the present status of direct delivery of stem cells or their derivative cardiomyocytes to the heart and the particular challenges each cell type brings, and consider where we should go from here.

Therapeutic Angiogenesis by Transplantation of Human Embryonic Stem Cell-Derived CD133 + Endothelial Progenitor Cells for Cardiac Repair

This study aim to enhance endothelial differentiation of human embryonic stem cells (hESCs) by transduction of an adenovirus (Ad) vector expressing hVEGF(165) gene (Ad-hVEGF(165) ). Purified hESC-derived CD133(+) endothelial progenitors were transplanted into a rat myocardial infarct model to assess their ability to contribute to heart regeneration. Optimal transduction efficiency with high cell viability was achieved by exposing differentiating hESCs to viral particles at a ratio of 1:500 for 4 h on three consecutive days. Reverse transcription-PCR analysis showed positive upregulation of VEGF, Ang-1, Flt-1, Tie-2, CD34, CD31, CD133 and Flk-1 gene expression in Ad-hVEGF(165) -transduced cells. Additionally, flow cytometric analysis of CD133, a cell surface marker, revealed an approximately fivefold increase of CD133 marker expression in Ad-hVEGF(165)-transduced cells compared with the nontransduced control. Within a rat myocardial infarct model, transplanted CD133(+) endothelial progenitor cells survived and participated, both actively and passively, in the regeneration of the infarcted myocardium, as seen by an approximately threefold increase in mature blood vessel density (13.62 +/- 1.56 vs 5.11 +/- 1.23; p < 0.01), as well as significantly reduced infarct size (28% +/- 8.2% vs 76% +/- 5.6%; p < 0.01) in the transplanted group compared with the culture medium-injected control. There was significant improvement in heart function 6 weeks post-transplantation, as confirmed by regional blood-flow analysis (1.72 +/- 0.612 ml/min/g vs 0.8 +/- 0.256 ml/min/g; p < 0.05), as well as echocardiography assessment of left ventricular ejection fraction (60.855% +/- 7.7% vs 38.22 +/- 8.6%; p < 0.05) and fractional shortening (38.63% +/- 9.3% vs 25.2% +/- 7.11%; p < 0.05). hESC-derived CD133(+) endothelial progenitor cells can be utilized to regenerate the infarcted heart.