This Article Abstract Full Text (PDF) All Versions of this Article: 28/2/208    most recent ATVBAHA.107.155317v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dimmeler, S. Articles by Zeiher, A. M. Search for Related Content PubMed PubMed Citation Articles by Dimmeler, S. Articles by Zeiher, A. M. Related Collections Novel Mediators and Mechanisms in Angiogenesis and Vasculogenesis

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:208.)
© 2008 American Heart Association, Inc.

Brief Review

Cell-Based Therapy of Myocardial Infarction

Stefanie Dimmeler; Jana Burchfield; Andreas M. Zeiher

From Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Germany.

Correspondence to Dr Stefanie Dimmeler, Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de

Series Editor: Stefanie Dimmeler
Novel Mediators and Mechanisms in Angiogenesis and Vasculogenesis
ATVB In Focus

Previous Brief Reviews in this Series:

•Dimmeler S. Novel mediators and mechanisms in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol. 2005;25:2245.
•Ferguson JE, Kelley RW, Patterson C. Mechanisms of endothelial differentiation in embryonic vasculogenesis. Arterioscler Thromb Vasc Biol. 2005;25:2246–2254.
•Werner N, Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler Thromb Vasc Biol. 2006;26:257–266.
•van Hinsbergh VWM, Engelse MA, Quax PHA. Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler Thromb Vasc Biol. 2006;26:716–728.
•Sata M. Role of circulating vascular progenitors in angiogenesis, vascular healing, and pulmonary hypertension: lessons from animal models. Arterioscler Thromb Vasc Biol. 2006;26:1008–1014.

	Abstract

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
Cell-based therapy is a promising option for treatment of ischemic diseases. Several cell types have experimentally been shown to increase the functional recovery of the heart after ischemia by physically forming new blood vessels, differentiating to cardiac myocytes and—additionally or alternatively—by providing proangiogenic and antiapoptotic factors promoting tissue repair in a paracrine manner. Clinical studies preferentially used adult bone marrow–derived cells for the treatment of patients with acute myocardial infarction. Most of the studies suggested that cell therapy reduced the infarct size and improved cardiac contractile function. However, cell therapy is in its early stages, and various questions remain. For example, the identification of those patients who benefit most from cell therapy, the optimal cell type and number for patient with acute and chronic diseases, the best time and way of cell delivery, and the mechanisms of action by which cells exhibit beneficial effects, need to be further evaluated. Although no major safety concerns were raised during the initial clinical trials, several potential side effects need to be carefully monitored. The present review article summarizes the results of the clinical studies and discusses the open issues.

Cell based therapy is a promising option for treatment of ischemic diseases. Several cell types have been shown to increase the functional recovery of the heart after ischemia. The present review article summarizes the results of the experimental and clinical studies and discusses open questions in cell-based therapies.

Key Words: cell therapy • neovascularization • stem cells • acute myocardial infarction

	Introduction

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
Ischemic diseases remain one of the major causes of morbidity and mortality in the industrialized world despite the development of several new therapeutic modalities, such as improved pharmacological therapies and improved interventional strategies (eg, catheter-based reopening of vessels). Peripheral ischemic vascular disease is still associated with a high morbidity and impairment of quality of life, whereas cardiac ischemia leading to postinfarction heart failure particularly in patients with large myocardial infarction is associated with a high mortality. Over the last decade, it has become apparent that the heart possesses regenerating capacities with respect to cardiomyocytes and new blood vessel formation (for review see^1,2). Specifically, it has been shown that a sizeable fraction of cardiac myocytes "refreshes" the heart after injury insults like ischemia or pressure overload.³ Based on experimental data demonstrating that infusion or injection of stem/progenitor cells improves heart function after myocardial infarction and enhances blood flow in models of peripheral ischemia, clinical trials were initiated in 2001 to treat patients with peripheral or cardiac ischemia with circulating blood or bone marrow–derived cells. The present review article will summarize the experimental data and the clinical application of cell-based therapies focusing on patients with acute myocardial infarction, where most clinical data are available at present.

	Types of Stem Cells

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
Numerous studies have experimentally addressed the potential of different types of stem cells to augment neovascularization and cardiac repair or regeneration. In general, two types of stem cells should be discussed separately: embryonic stem cells and adult stem cells. Whereas embryonic stem cells clearly have the capacity to differentiate into a variety of cell types and give rise to tissues and organs, most adult stem cells are more specified (more lineage committed) and the use of adult stem cells for organogenesis appears to be rather limited. This review will focus on the different types of adult stem cells and their therapeutic role in the salvage of ischemic tissue and in treatment of heart disease. Adult stem cells comprise at least 3 different groups: bone marrow–derived stem cells, the circulating pool of stem or progenitor cells, which, at least in part, are derived from the bone marrow, and tissue-resident stem cells.

Bone marrow–derived stem cells are the best characterized and have been used in the majority of clinical trials performed to date. Bone marrow contains a complex assortment of progenitor cells, including hematopoietic stem cells (HSCs); so-called "side population cells" (SP cells, defined by the expression of the Abcg2 transporter allowing to export a Hoechst dye),⁴ mesenchymal stem cells (MSCs) or stromal cells,⁵ and multipotential adult progenitor cells (MAPCs), a subset of MSCs.⁶ Several studies have shown the incorporation of these different bone marrow–derived cells into ischemic tissue, and it appears that these cells play a distinct role in the salvage of damaged tissue.

Another population of progenitor cells that has also been shown to have therapeutic potential is the pool of progenitor cells circulating within the blood. Circulating progenitor cells were initially discovered, when searching for proangiogenic cells for therapeutic vasculogenesis. Asahara and Isner isolated the so called "endothelial progenitor cells" defined by their function to form new blood vessels and enhance neovascularization after ischemia (for review see^7,8). According to the assumption that these cells may represent adult hemangioblasts, these cells were characterized by the expression of at least 2 hematopoietic stem cell markers (CD133⁺or CD34⁺) and the endothelial marker VEGF-receptor 2 (also known as KDR or flk-1). The use of the marker combination CD34⁺CD133⁺KDR⁺ to identify clonally expandable circulating progenitor cells with a high capacity to acquire an endothelial phenotype has recently been challenged, and in vitro studies suggested that CD34⁺/CD45^– cells have a higher capacity to acquire an endothelial phenotype, whereas CD34+CD133+KDR+ do not differentiate to endothelial cells.⁹ Although it is not entirely clear to what extent these data can be translated into the in vivo situation, where ischemic/necrotic tissue may provide an entirely different environment to dictate cell fate, it is evident from various studies that circulating progenitor cells, particularly when cultured in vitro, comprise several different cell populations. Whereas individual cells may indeed have clonal potential and stem cell characteristics, other cells may provide proangiogenic factors or promote vessel maturation or may act as pericytes together leading to neovascularization. For example, one subpopulation within these cultured or endogenously circulating cells consists of myeloid and myeloid precursor cells, which may preferentially act as proangiogenic cells,^10,11 in addition (or alternatively) to their capacity to differentiate to endothelial cells.^7,12 Alternatively, myeloid cells have been shown to fuse with skeletal muscle myotubes^13,14 indicating that myeloid subpopulations may not only act to mediate neovascularization, but may also aid in muscle regeneration. Therefore, the so called "endothelial progenitor cells" most likely consist of several cell types that together may mediate salvage of ischemic tissue. As such the term "endothelial progenitor cells" refers to one functional aspect of a heterogeneous cell population, which is capable to induce neovascularization.

Other populations of stem cells that have been shown to have therapeutic potential in the setting of ischemia are derived from tissue and include mesoangioblasts, both mesenchymal and endothelial progenitor cells derived from adipose tissue, and tissue-resident cardiac stem cells. Mesoangioblasts are vessel-associated multipotent progenitors that express the key marker of angiopoietic progenitors, VEGF-receptor 2, but are distinct from hematopoietic endothelial progenitor cells. In vitro mesoangioblasts differentiate into many mesoderm cell types, such as smooth, cardiac and striated muscle, bone and endothelium, and have been shown in vivo to improve skeletal muscle function in a muscular dystrophy model as well as to improve heart function.^15,16 Adipose tissue is a rich source of distinct subsets of stem/progenitor cells potentially useful for cardiac repair and neovascularization improvement.^17,18 Both, mesenchymal stem cells and endothelial progenitor cells were isolated after enzymatic digestion of adipose tissue and showed beneficial effects in experimental studies.

The discovery of tissue-resident stem cells in the heart, the "cardiac stem" cells, offers the potential for in vivo induction of proliferation and differentiation of these cells, which are primed to acquire a cardiac phenotype and, therefore, might be optimally suited for cardiac repair. Several different populations have been identified and characterized including c-Kit+ cells,¹⁹ Sca-1+ cells,²⁰ side population cells (SP),²¹ and cells expressing the protein Islet-1.²² Whereas c-Kit+ cells, Sca-1+ cells, and cardiac SP cells have been isolated from adult hearts, cells expressing Islet-1 so far only have been detected in neonatal hearts. Whether c-Kit+, Sca-1+, and cardiac SP cells comprise 3 different cell populations is not entirely clear. Another type of cardiac stem cell has been identified by growing self-adherent clusters (termed "cardiospheres") from subcultures of murine or human biopsy specimens.^23,24 Others have generated cardiac SP-cell derived cardiospheres by adapting a method used for creating neurospheres suggesting that cardiac neural crest cells may contribute to cardiac SP cells.²⁵ Cardiosphere-derived cardiac stem cells as well as c-Kit+ cardiac stem cells are capable of long-term self-renewal and can differentiate into the major specialized cell types of the heart: myocytes and vascular cells expressing both endothelial or smooth muscle cell markers. The exact origin of these c-Kit⁺, Sca-1⁺, SP, Islet-1⁺, or cardiosphere-derived cardiac stem cells and the mechanisms maintaining the cardiac stem cell pool are unclear. Two recent studies suggest that c-Kit⁺ and cardiac SP cells may arise from the bone marrow,^26,27 however these studies cannot entirely exclude that specific subpopulations of cardiac stem cells originate from the heart and these cardiac stem cells may represent remnants from embryonic development in selected niches within the heart.

In summary, although several different types of adult stems have been identified and used for improving cardiac function after ischemia, it remains unclear which of these cells have the greatest therapeutic potential. In an attempt to discern which adult stem cell population produces the greatest functional efficacy, one study compared mesoangioblasts and bone marrow–derived progenitor cells with fibroblasts and endothelial cells. Both cell types showed a similar capacity to improve heart function, whereas endothelial cells and fibroblasts were not effective.¹⁶ A single nonhematopoetic MSC subpopulation, unpurified MSC, bone marrow mononuclear cells, and peripheral blood mononuclear cells were compared in another study. This study suggested that single clonally purified MSC are most efficient for cardiac repair. Interestingly, unpurified MSC had similar beneficial effects on adverse remodeling of infarcted hearts compared with freshly isolated bone marrow mononuclear cells.²⁸ However, because the rats were treated with cyclosporin A, one cannot exclude that the immunosuppression itself modulated the effects of the different stem cell populations. Clearly, a ranking of cells used for cell therapy will not only be based on the assessment of the functional capacities of the cells, but also on the safety and feasibility of the treatment in the clinical setting.

	Clinical Application

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
Clinically Used Cell Types
Currently, a variety of autologous adult progenitor cells are undergoing preclinical evaluation. Bone marrow is, at present, the most frequent source used clinically for cardiac repair.²⁹ The rapid transition from bench to bedside was facilitated by the more than 30 years of clinical experience and the excellent safety profile of infused bone marrow–derived mononuclear cells (BMCs) used for bone marrow reconstitution. After bone marrow aspiration the mononuclear cell fraction is obtained by density gradient centrifugation in most of the studies (only the BOOST trial used a sedimentation protocol). The mononuclear fraction includes a heterogeneous mixture of cells with varying percentages of hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, and side population cells. So far, isolated bone marrow–derived cells are injected into the heart without further ex vivo expansion. In a few studies, specific subpopulations such as a fraction of hematopoietic and endothelial progenitor cells expressing the marker protein CD133⁺ are purified. Lastly, peripheral blood–derived progenitor cells are clinically used both for cardiac repair and peripheral ischemia. Circulating blood–derived cells have been isolated from mononuclear blood cells and selected ex vivo by culturing in "endothelium-specific" medium for 3 days,^30,31 or a specific subfraction, the hematopoietic progenitor cells CD34⁺, is enriched from whole blood after G colony–stimulating factor (CSF) mediated mobilization from the bone marrow into the blood.³²

Clinical Results
The results of clinical trials published to date, aiming at progenitor cell-based myocardial repair in patients with acute myocardial infarction, are summarized in the Table. Overall, the published studies demonstrate that the intracoronary infusion of autologous BMC is safe and feasible in patients with acute myocardial infarction. The initial pilot studies by Strauer,³³ the TOPCARE-AMI,³⁰ the BOOST-trial,³⁴ and the study performed by Fernandez-Aviles³⁵ reported nearly identical results—an improvement in global LV ejection fraction by an absolute 6 to 9 percentage point, reduced end-systolic LV volumes, and improved perfusion in the infarcted area 4 to 6 months after cell transplantation. A randomized controlled trial by Janssens³⁶ did not reveal a significant effect on global ejection fraction, but showed an improvement in regional ejection fraction and a reduction of the infarct size in the BMC group. Only one larger study, the ASTAMI trial, did not show any benefit on left ventricular functional parameters.³⁷ The reason for the failure of the ASTAMI trial to show a benefit of cell therapy may have been because of the different cell isolation and storage protocol, which significantly affected the functional capacity of the cells.³⁸ Because, however, no preclinical functional testing of the cells used for the ASTAMI trial was reported, it is essentially impossible to judge the negative outcome of this trial.

View this table: [in this window] [in a new window]   Table. Acute Myocardial Infarction

The beneficial effects observed in most of the pilot phase I/II studies were confirmed in the so far largest double-blind, randomized, multicenter REPAIR-AMI trial.³⁹ This study used BMCs and demonstrated a significant improvement of global and regional ejection fraction in the BMC group (+5.5 percentage points) compared with placebo (+3 percentage points) 4 months after follow-up. Endsystolic volumes significantly increased in the placebo group but remained unchanged in the BMC group. Interestingly, although the study was not powered to address a potential benefit on clinical end points, the incidence of the cumulative end point death, recurrence of myocardial infarction, and rehospitalization for heart failure was significantly lower in the BMC-treated patients compared with placebo after 1 year follow-up.^39,40

What variables might influence outcome? The larger number of patients enrolled in the REPAIR-AMI trial allowed to test several predefined secondary end points to generate hypothesis for the next generation trials. There was a significant interaction between the baseline ejection fraction and the improvement seen after BMC therapy. Patients with a lower baseline ejection fraction (48.9%) showed a significant 3-fold higher recovery in global ejection fraction indicating that patients with more severe myocardial infarction profit most from BMC therapy. Indeed, the beneficial effect on clinical end points was also preferentially observed in those patients with a lower baseline ejection fraction after myocardial infarction. These results confirmed the previous observation of the TOPCARE-AMI pilot trial.⁴¹ A second predefined end point addressed the question, whether the timing of BMC delivery affects the outcome. Surprisingly, patients being treated up to 4 days after the myocardial infarction showed no benefit, whereas later treatment (day 4 to 8) provided an enhanced improvement of ejection fraction during follow-up. Given that several experimental studies demonstrated that the cells provide cytoprotection coinciding with a reduction of cardiomyocyte apoptosis one would have expected that early timing of cell infusion would be most efficient. With the data of the REPAIR-AMI trial, one may speculate that the microenvironment after acute myocardial infarction changes during the first week after reperfusion, thereby modulating the homing or the subsequent functional activity of the infused cells.³⁹ It is well known that ischemia/reperfusion induces a transient change in the expression of chemoattractive factors such as VEGF and SDF-1, which are known to be essential for stimulating the recruitment and retention of cells in the tissue. Moreover, the initial edema formation is followed by a transient invasion of different "waves" of cells. Therefore, it is conceivable that cell homing might be best after a few days rather than immediately after reperfusion. Further studies are warranted to prospectively address this question.

Safety and Long Term Benefit of Cell Therapy
Although the initial experimental studies confirmed that infusion of bone marrow–derived mononuclear cells or CD34+ does not cause major side effects, several potential issues were raised during the last years including a potential effect of cell therapy on electrical stability, increased restenosis, or progression of atherosclerotic disease. However, none of the clinical studies with BMCs so far reported an increased incidence of arrhythmias (as have been seen in some of the myoblast trials). Moreover, restenosis, which was considered as potential side effect by progenitor cell–mediated plaque angiogenesis or plaque inflammation,⁴² was only increased in one study using CD133⁺ cells.⁴³ This is surprising, because the isolation of selected progenitor cells excluding contaminating proinflammatory cells would have been assumed to reduce rather than increase the risk of restenosis and atherosclerotic disease progression. Because CD133⁺ cells were isolated by using a mouse antibody, one may speculate that the remaining antibody might have elicited a local proinflammatory reaction despite the failure to detect systemic anti-mouse antibodies in the patients. All other studies did not observe an augmented risk for restenosis^34,44; if anything, there was a decreased necessity for revascularization procedures in the REPAIR-AMI trial.³⁹

Intramyocardial calcification was reported to occur in murine models of myocardial infarction after direct injection of unpurified bone marrow cells or mesenchymal stem cells.^45,46 In the various clinical trials, none of the investigators reported the occurrence of calcifications by MRI imaging. This may be explained by the enrichment of mononuclear cells by density gradient centrifugation used in the majority of the clinical studies. Indeed, in a side-by-side comparison, only unfractionated bone marrow cells and MSC, but not purified hematopoietic progenitor cell injection did induce pathological abnormalities and calcification in experimental models.⁴⁶

Overall, the clinical data available at present indicate that cell therapy with bone marrow–derived cells is feasible and safe at least for the duration of follow-up presently available (up to 5 years for the initial studies). It had been discussed that the proangiogenic capacity particularly of EPC might relate to an increased tumor vascularization. Although it is unclear whether a single application of EPC is sufficient to promote tumor growth, most of the clinical trials did exclude patients with known tumors. During follow-up of the available studies, no increased incidence of cancer was seen in BMC-treated patient. However, because of the low incidence of such events, this needs to be carefully monitored in the future.

An important issue is whether the improvement seen during the initial 6 months after cell therapy is maintained for a prolonged time. Careful evaluation of the 18 months follow-up data of the BOOST trial indicates that the ejection fraction of the cell therapy group is maintained from 6 to 18 months follow-up, however the difference between the cell therapy and the control group was no longer statistically significant. The small number of patients (30 per group) may preclude detecting a statistical difference between the 2 groups. The long term 5 years follow-up MRI-derived data of the TOPCARE-AMI trial showed that the ejection fraction is maintained and even further augmented in the treated patients, in parallel with a sustained reduction in NT-proBNP serum levels suggesting a sustained beneficial effect on long term left ventricular remodeling (S.D. and A.M.Z., unpublished data). However, longer term follow up in larger scale randomized trials will finally address this important question. In addition, repetitive treatment might be an option in case cell therapy provides only a transient benefit. Finally, preliminary as yet unpublished results suggested that the intravenous infusion of nonautologous mesenchymal bone-marrow derived cells may have some effects in patients with anterior myocardial infarction. Such an off-the-shelf strategy for cell therapy would potentially make the procedural logistics easier.

	Mechanisms of Action

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
One of the most urgent questions in basic science, to elucidate the mechanism by which stem/progenitor cells achieve a functional improvement, is difficult to be tested in the clinical scenario. Although clinicians can measure flow reserve and heart function, the underlying detailed mechanism cannot be determined with an ethically applicable technology in the near future. The demonstration of improvement of neovascularization by bone marrow–derived mononuclear cells and endothelial progenitor cells is, historically, the inception of virtually all cell-based therapies using bone marrow or its circulating derivatives for myocardial ischemia. It has been shown, using a variety of progenitor/stem cell populations, that these cells contribute to neovascularization. Neovascularization can be mediated by the physical incorporation of progenitor cells into new capillaries⁴⁷ or by perivascular accumulation of cells. Furthermore, incorporated progenitor cells, of most, if not all types, may release growth factors that promote angiogenesis by acting on mature endothelial cells.^10,48 The extent to which progenitor cells contribute to vasculogenesis by becoming physical elements of newly formed vessels versus acting through secreted factors may plausibly depend on the environment to which the cells are exposed, and may in part depend on the applied cell type. This may explain the large difference in endothelial incorporation detected in different experimental studies. However, human bone marrow–derived endothelial progenitor cells were shown to exert both classes of effects and most experimental studies, which applied cells for therapeutic neovascularization, demonstrated a rate of incorporated cells in capillaries between 2% to 29% after cell therapy.⁷ The Doppler substudy of the REPAIR-AMI trial provided convincing clinical evidence that intracoronary BMC administration in patients with acute myocardial infarction is associated with profound improvements in vascular conductance capacity and microvascular function in the cell-treated coronary territory.⁴⁹ It will be important to determine whether increased coronary vascular conductance capacity ultimately translates into improved clinical outcome to establish a cause-and-effect relationship between cell therapy–based improvements in neovascularization and functional cardiac regeneration.

In addition to enhanced neovascularization, activating cytoprotection must be considered as among the most important possible consequences of cell-based therapies. Paracrine factors may beneficially influence cardiac repair by protecting cardiac myocytes from apoptotic stimuli or activate cardiac-resident stem cells to enhance the endogenous repair capacity.^48,50,51 In a porcine model of myocardial infarction, transplantation of allogeneic mesenchymal stem cells, in the absence of definitive cardiac myocyte differentiation, led to cardiac myocyte cell cycle entry and decreased apoptosis suggesting the stem cell transplantation may activate cardiac-resident stem cells to enhance endogenous repair.⁵² Indeed, soluble factors released by ex vivo cultured human EPCs stimulated migration of cardiac stem cells in vitro.⁴⁸

Dysregulated inflammation in the heart after myocardial infarction is considered to be a normal part of the healing process after ischemic injury, which might be modulated by administered cell therapy. Indeed, analysis of gene expression profiles revealed that genes, which are involved in the inflammatory response under hypoxic conditions are highly expressed in BMCs. An antiinflammatory role for administrated MSCs was demonstrated at 4 weeks after myocardial infarction with the downregulation of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, cytokines known to be involved in adverse LV remodeling.⁵³ Thus suppression of inflammation during remodelling most likely will contribute to the improvement in LV function and the attenuation of adverse LV remodeling. In fact, several reports have shown that myocardial transplantation of progenitor/stem cells leads to a decrease in myocardial fibrosis after myocardial infarction.^47,54 However, it is unclear whether the stem cell–mediated decrease in fibrosis is a secondary effect to limited cardiac myocyte apoptosis thereby negating the need for synthesis of a provisional extracellular matrix, or whether stem cells have a direct effect on extracellular matrix remodelling. At least MSCs were shown to directly attenuate cardiac fibroblast proliferation and collagen synthesis via the release of paracrine factors in vitro.⁵⁵ Whether other progenitor/stem cell populations or their secreted factors modulate other extracellular matrix proteins or modulate the differentiation of fibroblasts into myofibroblasts, the cell responsible for collagen deposition, has not been investigated so far.

Experimental studies addressing the capacity of transplanted bone marrow–derived stem cells to differentiate into the cardiomyogenic lineage yielded conflicting results.^1,56,57 In contrast to ES cells, most adult stem or progenitor cells do not spontaneously differentiate into cardiomyocytes but rather require an adequate stimulus to do so. The local microenvironment plays an important role to induce cell fate changes by physical cell-to-cell interaction or by providing paracrine factors. A recent study supports this notion by demonstrating that endogenous replacement of cardiomyocytes only occurs after injury.³ The identification of subsets of adult stem cells with a higher capacity to differentiate into cardiac myocytes and the enhancement of cardiac differentiation by interacting with the pathways controlling differentiation are currently under investigation.

It is essential to distinguish between the target patient populations, eg, acute versus chronic ischemia, when discussing mechanisms considered to improve functional recovery, because fundamentally different pathophysiological processes are targeted. In patients with acute myocardial infarction, progenitor cell transplantation aims to prevent or ameliorate postinfarction left ventricular remodeling, thereby reducing postinfarction heart failure. Such an effect might even be achieved by enhanced neovascularization and reduced cardiomyocyte apoptosis, irrespective of long-term engraftment and transdifferentiation. Conversely, the former 2 mechanisms acting alone may have limited benefit in patients with long-established scars, absent hibernating myocytes and end-stage heart failure, where cardiomyogenesis in its pure sense would be desirable. Thus, the putative mechanisms underlying cell therapy–mediated functional recovery of the heart illustrated in the Figure may differ with respect to the clinical relevance in different entities of cardiac failure.

View larger version (27K): [in this window] [in a new window]   Figure. Proposed mechanisms of action of stem/progenitor cells in cardiovascular repair.

	Outlook: Open Questions

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
In acute myocardial infarction, the established safety and proof-of-concept studies provide a cogent rationale for larger, randomized trials addressing the question whether cellular therapy aimed at cardiac repair not only improves pump function, but also reduces mortality and morbidity. In planning such clinical outcome trials, one should take into account that aggressive reperfusion strategies in acute myocardial infarction have dramatically improved prognosis for those patients, in which reperfusion is associated with recovery of contractile function. In contrast, for patients with failure of contractile recovery despite successful reperfusion, which constitute approximately 20% of the entire cohort of patients with STEMI, mortality and morbidity are still markedly increased, and this has not changed over the last 15 years.^58,59 Thus, this patient population will be the primary target to establish a potential clinical relevance of cell-based therapies in patients with acute myocardial infarction. Moreover, several open-ended questions are likely to be answered in the future: (1) What is the optimal time of cell delivery after acute myocardial infarction? (2) Is there a dose response relationship? and (3) How do different cell types compare? Clearly, bone marrow–derived cells have set the stage and have provided beneficial effects in various studies. However, the extent to which ejection fraction is improved, particularly in patients with chronic heart failure, is limited.⁶⁰ Therefore, additional cell types will enter the clinical arena: adipose tissue–derived stem cells, multipotential cells from bone marrow or skeletal muscle (minuscule subpopulations, distinct from the unfractionated bone marrow and the myoblasts in current trials), somatic stem cells from placental cord blood, and cardiac-resident progenitor cells that have a heightened predisposition to adopt the cardiac muscle fate. However, whether the experimentally suggested promise of augmented cardiac myogenesis will translate into enhanced contractile function, when applying these cells in patients with chronic heart failure, is currently unknown.

More complex and challenging are a series of pathobiological concerns, sending the scientific community from bedside to bench and back again. As long as patients’ own cells are used in the autologous setting, certain patients’ cells may be unsatisfactory, in their naïve and unmanipulated state, prompting systematic dissection of each step in progenitor cell function. Cell enhancement strategies to improve patient-derived cells by pretreatment with small molecules or genetic modification may contribute to an augmented recruitment as well as in the future may enhance differentiation or other beneficial functions.

Clearly, the use of stem/progenitor cells for cardiac repair is currently not at a stage to be used in routine clinical practice. Despite a wealth of experimental and clinical data suggesting feasibility, safety, and even early clinical efficacy in patients with acute myocardial infarction, progression to widespread clinical application of progenitor cell administration to promote functional cardiac regeneration must be balanced against the inherent risk of testing a novel therapy. As such, attempts of regenerative therapeutic interventions in patients with significant cardiac dysfunction should proceed in controlled trials with the utmost rigorous scientific and ethical standards, paralleled by further extensive in vitro and animal studies. Such a strategy will not only maximize patient safety, which is of paramount interest, but will also generate reciprocal insights into mechanisms and potential shortcomings of cell-based therapies aiming at functional cardiac regeneration. Specific attention should be given to the processing of the cells and to ascertain their functionality for regenerative purposes before initiating their clinical application. The promise of functional cardiac regeneration by cell-based therapies offers novel opportunities to address the large unmet clinical need of treating patients with severe cardiac dysfunction.

	Acknowledgments

 
Sources of Funding

The work of the applicant was supported by grants from the Leducq Foundation and the Deutsche Forschungsgemeinschaft (DFG, FOR501).

Disclosures

S.D. and A.M.Z. are founders and advisors of t2cure GmbH.

	Footnotes

 
Original received September 3, 2007; final version accepted October 9, 2007.

	References

Top Abstract Introduction Types of Stem Cells Clinical Application Mechanisms of Action Outlook: Open Questions References

 
1. Anversa P, Leri A, Rota M, Hosoda T, Bearzi C, Urbanek K, Kajstura J, Bolli R. Concise review: stem cells, myocardial regeneration, and methodological artifacts. Stem Cells. 2007; 25: 589–601.[CrossRef][Medline] [Order article via Infotrieve]

2. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest. 2005; 115: 572–583.[CrossRef][Medline] [Order article via Infotrieve]

3. Hsieh PC, Segers VF, Davis ME, Macgillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007; 13: 970–974.[CrossRef][Medline] [Order article via Infotrieve]

4. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001; 107: 1395–1402.[CrossRef][Medline] [Order article via Infotrieve]

5. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105: 93–98.[Abstract/Free Full Text]

6. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002; 418: 41–49.[CrossRef][Medline] [Order article via Infotrieve]

7. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004; 95: 343–353.[Abstract/Free Full Text]

8. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med. 2003; 9: 702–712.[CrossRef][Medline] [Order article via Infotrieve]

9. Case J, Mead LE, Bessler WK, Prater D, White HA, Saadatzadeh MR, Bhavsar JR, Yoder MC, Haneline LS, Ingram DA. Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol. 2007; 35: 1109–1118.[CrossRef][Medline] [Order article via Infotrieve]

10. Rehman J, Li J, Orschell CM, March KL. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003; 107: 1164–1169.[Abstract/Free Full Text]

11. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramovitch R, Keshet E. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell. 2006; 124: 175–189.[CrossRef][Medline] [Order article via Infotrieve]

12. Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH, Grompe M, Fleming WH. Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci U S A. 2006; 103: 13156–13161.[Abstract/Free Full Text]

13. Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med. 2003; 9: 1520–1527.[CrossRef][Medline] [Order article via Infotrieve]

14. Sacco A, Doyonnas R, LaBarge MA, Hammer MM, Kraft P, Blau HM. IGF-I increases bone marrow contribution to adult skeletal muscle and enhances the fusion of myelomonocytic precursors. J Cell Biol. 2005; 171: 483–492.[Abstract/Free Full Text]

15. Galvez BG, Sampaolesi M, Brunelli S, Covarello D, Gavina M, Rossi B, Costantin G, Torrente Y, Cossu G. Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. J Cell Biol. 2006; 174: 231–243.[Abstract/Free Full Text]

16. Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F, Chimenti S, Cusella G, Dejana E, Cossu G, Latini R. Mesoangioblasts, vessel-associated multipotent stem cells, repair the infarcted heart by multiple cellular mechanisms: a comparison with bone marrow progenitors, fibroblasts, and endothelial cells. Arterioscler Thromb Vasc Biol. 2005; 25: 692–697.[Abstract/Free Full Text]

17. Fraser JK, Schreiber R, Strem B, Zhu M, Alfonso Z, Wulur I, Hedrick MH Plasticity of human adipose stem cells toward endothelial cells and cardiomyocytes. Nat Clin Pract Cardiovasc Med. 2006; 3 (Suppl 1): S33–S37.[CrossRef][Medline] [Order article via Infotrieve]

18. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002; 13: 4279–4295.[Abstract/Free Full Text]

19. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003; 114: 763–776.[CrossRef][Medline] [Order article via Infotrieve]

20. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD. Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A. 2003; 100: 12313–12318.[Abstract/Free Full Text]

21. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002; 530: 239–243.[CrossRef][Medline] [Order article via Infotrieve]

22. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature. 2005; 433: 647–653.[CrossRef][Medline] [Order article via Infotrieve]

23. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004; 95: 911–921.[Abstract/Free Full Text]

24. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marban E. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007; 115: 896–908.[Abstract/Free Full Text]

25. Tomita Y, Matsumura K, Wakamatsu Y, Matsuzaki Y, Shibuya I, Kawaguchi H, Ieda M, Kanakubo S, Shimazaki T, Ogawa S, Osumi N, Okano H, Fukuda K. Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart. J Cell Biol. 2005; 170: 1135–1146.[Abstract/Free Full Text]

26. Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, Verma S, Weisel RD, Keating A, Li RK. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest. 2006; 116: 1865–1877.[CrossRef][Medline] [Order article via Infotrieve]

27. Mouquet F, Pfister O, Jain M, Oikonomopoulos A, Ngoy S, Summer R, Fine A, Liao R. Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow–derived stem cells. Circ Res. 2005; 97: 1090–1092.[Abstract/Free Full Text]

28. Zhang S, Ge J, Sun A, Xu D, Qian J, Lin J, Zhao Y, Hu H, Li Y, Wang K, Zou Y. Comparison of various kinds of bone marrow stem cells for the repair of infarcted myocardium: single clonally purified non-hematopoietic mesenchymal stem cells serve as a superior source. J Cell Biochem. 2006; 99: 1132–1147.[CrossRef][Medline] [Order article via Infotrieve]

29. Schachinger V, Tonn T, Dimmeler S, Zeiher AM Bone-marrow-derived progenitor cell therapy in need of proof of concept: design of the REPAIR-AMI trial. Nat Clin Pract Cardiovasc Med. 2006; 3 Suppl 1: S23–S28.[CrossRef][Medline] [Order article via Infotrieve]

30. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002; 106: 3009–3017.[Abstract/Free Full Text]

31. Erbs S, Linke A, Schuler G, Hambrecht R. Intracoronary administration of circulating blood-derived progenitor cells after recanalization of chronic coronary artery occlusion improves endothelial function. Circ Res. 2006; 98: e48.[Free Full Text]

32. Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007; 115: 3165–3172.[Abstract/Free Full Text]

33. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002; 106: 1913–1918.[Abstract/Free Full Text]

34. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004; 364: 141–148.[CrossRef][Medline] [Order article via Infotrieve]

35. Fernandez-Aviles F, San Roman JA, Garcia-Frade J, Fernandez ME, Penarrubia MJ, de la Fuente L, Gomez-Bueno M, Cantalapiedra A, Fernandez J, Gutierrez O, Sanchez PL, Hernandez C, Sanz R, Garcia-Sancho J, Sanchez A. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res. 2004; 95: 742–748.[Abstract/Free Full Text]

36. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F. Autologous bone marrow–derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006; 367: 113–121.[CrossRef][Medline] [Order article via Infotrieve]

37. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Forfang K. Autologous stem cell transplantation in acute myocardial infarction: The ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J. 2005; 39: 150–158.[CrossRef][Medline] [Order article via Infotrieve]

38. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J. 2007.

39. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006; 355: 1210–1221.[Abstract/Free Full Text]

40. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Werner N, Haase J, Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006; 27: 2775–2783.[Abstract/Free Full Text]

41. Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004; 44: 1690–1699.[Abstract/Free Full Text]

42. Silvestre JS, Gojova A, Brun V, Potteaux S, Esposito B, Duriez M, Clergue M, Le Ricousse-Roussanne S, Barateau V, Merval R, Groux H, Tobelem G, Levy B, Tedgui A, Mallat Z. Transplantation of bone marrow–derived mononuclear cells in ischemic apolipoprotein E-knockout mice accelerates atherosclerosis without altering plaque composition. Circulation. 2003; 108: 2839–2842.[Abstract/Free Full Text]

43. Mansour S, Vanderheyden M, De Bruyne B, Vandekerckhove B, Delrue L, Van Haute I, Heyndrickx G, Carlier S, Rodriguez-Granillo G, Wijns W, Bartunek J. Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction. J Am Coll Cardiol. 2006; 47: 1727–1730.[Free Full Text]

44. Assmus B, Walter DH, Lehmann R, Honold J, Martin H, Dimmeler S, Zeiher AM, Schachinger V. Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction. Eur Heart J. 2006; 27: 2989–2995.[Abstract/Free Full Text]

45. Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW. Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation. 2004; 109: 3154–3157.[Abstract/Free Full Text]

46. Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, Fries JW, Tiemann K, Bohlen H, Hescheler J, Welz A, Bloch W, Jacobsen SE, Fleischmann BK. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007; 110: 1362–1369.[Abstract/Free Full Text]

47. Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, Uchida S, Masuo O, Iwaguro H, Ma H, Hanley A, Silver M, Kearney M, Losordo DW, Isner JM, Asahara T. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 2003; 107: 461–468.[Abstract/Free Full Text]

48. Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005; 39: 733–742.[CrossRef][Medline] [Order article via Infotrieve]

49. Erbs S, Linke A, Schachinger V, Assmus B, Thiele H, Diederich KW, Hoffmann C, Dimmeler S, Tonn T, Hambrecht R, Zeiher AM, Schuler G. Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation. 2007; 116: 366–374.[Abstract/Free Full Text]

50. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005; 11: 367–368.[CrossRef][Medline] [Order article via Infotrieve]

51. Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 2006; 98: 1414–1421.[Abstract/Free Full Text]

52. Mazhari R, Hare JM. Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche. Nat Clin Pract Cardiovasc Med. 2007; 4 Suppl 1: S21–S26.[CrossRef][Medline] [Order article via Infotrieve]

53. Le Blanc K. Mesenchymal stromal cells: Tissue repair and immune modulation. Cytotherapy. 2006; 8: 559–561.[CrossRef][Medline] [Order article via Infotrieve]

54. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.[CrossRef][Medline] [Order article via Infotrieve]

55. Ohnishi S, Sumiyoshi H, Kitamura S, Nagaya N. Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions. FEBS Lett. 2007; 581: 3961–3966.[CrossRef][Medline] [Order article via Infotrieve]

56. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410: 701–705.[CrossRef][Medline] [Order article via Infotrieve]

57. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004; 428: 664–668.[CrossRef][Medline] [Order article via Infotrieve]

58. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis. Results of the GISSI-2 data base. The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-2 Data Base. Circulation. 1993; 88: 416–429.[Abstract/Free Full Text]

59. Halkin A, Singh M, Nikolsky E, Grines CL, Tcheng JE, Garcia E, Cox DA, Turco M, Stuckey TD, Na Y, Lansky AJ, Gersh BJ, O’Neill WW, Mehran R, Stone GW. Prediction of mortality after primary percutaneous coronary intervention for acute myocardial infarction: the CADILLAC risk score. J Am Coll Cardiol. 2005; 45: 1397–1405.[Abstract/Free Full Text]

60. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006; 355: 1222–1232.[Abstract/Free Full Text]

This article has been cited by other articles:

				F. H. Seeger, T. Rasper, M. Koyanagi, H. Fox, A. M. Zeiher, and S. Dimmeler CXCR4 Expression Determines Functional Activity of Bone Marrow-Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1802 - 1809. [Abstract] [Full Text] [PDF]

				M. E. Padin-Iruegas, Y. Misao, M. E. Davis, V. F.M. Segers, G. Esposito, T. Tokunou, K. Urbanek, T. Hosoda, M. Rota, P. Anversa, et al. Cardiac Progenitor Cells and Biotinylated Insulin-Like Growth Factor-1 Nanofibers Improve Endogenous and Exogenous Myocardial Regeneration After Infarction Circulation, September 8, 2009; 120(10): 876 - 887. [Abstract] [Full Text] [PDF]

				O. Dotsenko and M. Jahangiri Endogenous stem cells in patients undergoing coronary artery bypass graft surgery Eur. J. Cardiothorac. Surg., September 1, 2009; 36(3): 563 - 571. [Abstract] [Full Text] [PDF]

				D. L. Kraitchman and J. W.M. Bulte In Vivo Imaging of Stem Cells and Beta Cells Using Direct Cell Labeling and Reporter Gene Methods Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1025 - 1030. [Abstract] [Full Text] [PDF]

				M. Tendera, W. Wojakowski, W. Ruzyllo, L. Chojnowska, C. Kepka, W. Tracz, P. Musialek, W. Piwowarska, J. Nessler, P. Buszman, et al. Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial Eur. Heart J., June 1, 2009; 30(11): 1313 - 1321. [Abstract] [Full Text] [PDF]

				D. P Sieveking and M. K. Ng Cell therapies for therapeutic angiogenesis: back to the bench Vascular Medicine, May 1, 2009; 14(2): 153 - 166. [Abstract] [PDF]

				S. Wisel, M. Khan, M. L. Kuppusamy, I. K. Mohan, S. M. Chacko, B. K. Rivera, B. C. Sun, K. Hideg, and P. Kuppusamy Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 543 - 550. [Abstract] [Full Text] [PDF]

				J. Lee, M. A. Stagg, S. Fukushima, G. K. R. Soppa, U. Siedlecka, S. J. Youssef, K. Suzuki, M. H. Yacoub, and C. M. N. Terracciano Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H927 - H936. [Abstract] [Full Text] [PDF]

				M. Tendera and W. Wojakowski Cell therapy--success does not come easy Eur. Heart J., March 2, 2009; 30(6): 640 - 641. [Full Text] [PDF]

				S. Ausoni and S. Sartore From fish to amphibians to mammals: in search of novel strategies to optimize cardiac regeneration J. Cell Biol., February 9, 2009; 184(3): 357 - 364. [Abstract] [Full Text] [PDF]

				R. L Kao, W. Browder, and C. Li Cellular Cardiomyoplasty: What Have We Learned? Asian Cardiovasc Thorac Ann, January 1, 2009; 17(1): 89 - 101. [Abstract] [Full Text] [PDF]

				S. Dimmeler and M. Tjwa Better Regenerative Output After Cellular Input: Healing Hearts by Combining Basic Fibroblast Factor and Cell-Based Therapy J. Am. Coll. Cardiol., December 2, 2008; 52(23): 1866 - 1868. [Full Text] [PDF]

				M. Ruel, A. F.R. Stewart, and E. J. Suuronen From Genes to Regenerative Medicine: Approaches in Development Circ. Res., November 7, 2008; 103(10): 1050 - 1052. [Full Text] [PDF]

				K. K. Hirschi, D. A. Ingram, and M. C. Yoder Assessing Identity, Phenotype, and Fate of Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1584 - 1595. [Full Text] [PDF]

				P. Tossios, B. Krausgrill, M. Schmidt, T. Fischer, M. Halbach, J. W.U. Fries, S. Fahnenstich, P. Frommolt, I. Heppelmann, A. Schmidt, et al. Role of balloon occlusion for mononuclear bone marrow cell deposition after intracoronary injection in pigs with reperfused myocardial infarction Eur. Heart J., August 1, 2008; 29(15): 1911 - 1921. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 28/2/208    most recent ATVBAHA.107.155317v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dimmeler, S. Articles by Zeiher, A. M. Search for Related Content PubMed PubMed Citation Articles by Dimmeler, S. Articles by Zeiher, A. M. Related Collections Novel Mediators and Mechanisms in Angiogenesis and Vasculogenesis