Abstract

In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischaemic heart disease. After the initial characterization of putative endothelial progenitor cells and their potential to promote cardiac neovascularization and to attenuate ischaemic injury, a decade of intense research has examined several novel approaches to promote cardiac repair in adult life. A variety of adult stem and progenitor cells from different sources have been examined for their potential to promote cardiac repair and regeneration. Although early, small-scale clinical studies underscored the potential effects of cell-based therapy largely by using bone marrow (BM)-derived cells, subsequent randomized-controlled trials have revealed mixed results that might relate, at least in part, to differences in study design and techniques, e.g. differences in patient population, cell sources and preparation, and endpoint selection. Recent meta-analyses have supported the notion that administration of BM-derived cells may improve cardiac function on top of standard therapy. At this stage, further optimization of cell-based therapy is urgently needed, and finally, large-scale clinical trials are required to eventually proof its clinical efficacy with respect to outcomes, i.e. morbidity and mortality. Despite all promises, pending uncertainties and practical limitations attenuate the therapeutic use of stem/progenitor cells for ischaemic heart disease. To advance the field forward, several important aspects need to be addressed in carefully designed studies: comparative studies may allow to discriminate superior cell populations, timing, dosing, priming of cells, and delivery mode for different applications. In order to predict benefit, influencing factors need to be identified with the aim to focus resources and efforts. Local retention and fate of cells in the therapeutic target zone must be improved. Further understanding of regenerative mechanisms will enable optimization at all levels. In this context, cell priming, bionanotechnology, and tissue engineering are emerging tools and may merge into a combined biological approach of ischaemic tissue repair.

Background

Treatment of acute myocardial infarction (AMI) and ischaemic cardiomyopathy includes rapid revascularization to limit ischaemic damage and consecutive left ventricular (LV) dysfunction and remodelling, and optimized secondary prevention strategies aiming to attenuate progression of cardiac dysfunction and vascular disease. As a result, the prevalence of heart failure from post-ischaemic cardiac dysfunction rather increases1 causing a substantial morbidity.2 Furthermore, despite modern medical therapy, there is a substantial number of patients with ischaemic heart disease refractory to current therapeutic approaches lacking further treatment options, i.e. patients with angina pectoris and no option of interventional or surgical revascularization.

After the initial description of putative endothelial progenitor cells (EPCs) more than a decade ago,3 extensive research in the field of regenerative medicine has undermined the long-standing dogma that some differentiated organs such as the heart cannot be repaired in post natal life. We are standing on the merge to the era of biological repair in ischaemic cardiovascular disease after the potential of cardiac repair by a variety of stem and progenitor cell populations has been revealed in pre-clinical and early clinical studies.

In the first part of this review, we recapitulate the status quo of adult cell-based therapy in ischaemic heart disease with a clear focus on randomized-controlled clinical trials where available. In addition, we chose to include smaller-size, uncontrolled clinical studies where randomized-controlled data are not available and interesting insights are suggested. Due to space limitations, we were unfortunately not able to include all clinical studies. In the second part, we critically reflect limitations, uncertainties, and challenges of current approaches before finally discussing potential roadmaps of future developments in the field of cell-based cardiac repair. For a comprehensive review of stem and progenitor cell biology, the reader is referred to other in-depth reviews.4–8

Clinical experience from cell-based therapy

By definition, stem cells are capable to self-renew and to generate progenitor cells that continue to differentiate into lineage-committed mature cells. Progenitor cells, hence, are more lineage-determined, and therefore carry a more limited differentiation potential and may proliferate for a finite number of divisions and lack a self-renewal capacity. In this nomenclature, CD133 is a marker of premature, rather undifferentiated, barely lineage-committed stem and progenitor cells that is lost early during differentiation, whereas expression of CD34 is maintained to later stages.

The therapeutic use of unselected bone marrow cells that contain stem and progenitor cells initially gained most momentum and has been evaluated farthest in the clinic setting. More recently, other adult stem and progenitor cells, such as circulating stem and progenitor cells, resident cardiac stem cells, and mesenchymal stem cells (MSCs) are being used in translational studies for clinical applications (Figure 1). Skeletal myoblasts (SMs) constitute another cell category that was considered suitable for cardiac repair. Each cell population seems to carry its own profile of advantages, disadvantages, practical limitations, and translational practicability.9

Figure 1

Clinically examined as well as emerging stem and progenitor containing cell populations, and their delivery routes for the treatment of ischaemic heart disease. 

Figure 1

Clinically examined as well as emerging stem and progenitor containing cell populations, and their delivery routes for the treatment of ischaemic heart disease. 

In the field of ischaemic heart disease, stem and progenitor cell-based therapies have been applied after AMI, after remote (chronic) myocardial infarction (CMI) with cardiac dysfunction and/or in ischaemic cardiomyopathy, and for patients with intractable (chronic) angina pectoris that is not amenable to revascularization and is refractory to medical therapy. Dependent on the targeted entity, different delivery routes have been used for cell transfer.

Delivery routes for stem and progenitor cell-based therapies

Conceptually, the goal is to safely deliver an optimal number of effective cells as selective as possible to the therapeutic target zone via a minimally invasive route. So far, cells have been transplanted into the heart overly via intracoronary infusion or intramyocardial injection (Figure 1).

Adapting the elegant, minimal-invasive technique lent from interventional cardiology for transvascular approaches, stem cells can be homogenously distributed via intracoronary infusion. To reduce spill-back and, in turn, optimize the contact time of cells and coronary vessel wall, cells are infused in block-balloon technique.10 This approach is only feasible in patients with a patent target vessel and, therefore, no option for non-revascularized areas. In addition, its efficiency is impaired by a complex multistep process of vessel adhesion and transmigration to allow infused stem cells to invade the tissue. Then, homing of invaded cells is also dependent on chemoattraction towards factors secreted from the ischaemic tissue.11 In line with this concept, cardiac homing of early EPCs after intracoronary infusion was increased in patients with an acute compared with chronic MI.12 As a side note, although intravenous infusion of stem/progenitor cells initially appeared effective,13 low target zone cell concentration due to off-target homing14 and biological redistribution15 strongly challenged this transvascular strategy which cannot be favoured anymore.

The more invasive intramyocardial cell injection, on the other hand, overcomes some of these hurdles and appears particularly suitable in the case of non-revascularized infarct-related vessels and/or ischaemic cardiomyopathy. Cells can be injected into the myocardium from the epimyocardial side, commonly during open-heart surgery, or endomyocardial side by means of needle-tipped delivery catheters. Detouring the bloodstream has also been particularly attractive for large cell types such as MSCs and SMs. On the downside, injection-related puncture of the viable or necrotic myocardium comes with some risk, i.e. of ventricular perforation. Further, injections lead to inhomogeneous distribution of cell clusters in malperfused tissue. In this scenario, an elegant and now commonly used catheter-based option is to guide the endomyocardial injection by electromechanical mapping (EMM, e.g. NOGA mapping). This technique enables to focus the cells to ischaemic but viable (hibernating) myocardium.

For the future advance, however, it has to be kept in mind from the clinician's perspective that the more invasive the technique and the higher percentage of co-morbidities introduced, the higher the procedural risk in this group of commonly elderly, multimorbid patients, who will be eligible for cell-based therapies.

Unselected bone marrow-derived cells

The use of unselected BM-derived mononuclear cells (BMCs) is clearly the most examined cardiac cell-based therapy in clinical studies (Figure 2) with a clinical follow-up experience up to 5 years.16 To some extent, this development is the result of the pragmatic attractiveness of BMCs: (i) BMCs are rather easy to harvest, (ii) yielded cell numbers do not limit clinical applications, (iii) while it remains unknown which cell types are more potent or have particular potent repair properties, BMCs contain an ‘un-narrowed’ composition of cells including fractions of stem and progenitor cells, and (iv) their preparation does not need prolonged ex vivo manipulation.

Figure 2

Selected completed and ongoing randomized-controlled clinical trials on cell-based therapy in ischaemic heart disease.

Figure 2

Selected completed and ongoing randomized-controlled clinical trials on cell-based therapy in ischaemic heart disease.

Acute myocardial infarction

After early-phase clinical studies had suggested the safety and feasibility of intracoronary BMC infusion after AMI,10,17–19 several mid-sized, randomized, partly placebo-controlled trials have generated mixed results. The randomized-controlled REPAIR-AMI and BOOST trials showed an improvement of global LV ejection fraction (LV-EF) without significant changes of LV end-diastolic volumes 4–6 months after cell transfer.20,21 A REPAIR-AMI substudy revealed that the increase in LV-EF did not occur at the expense of increases in end-systolic or end-diastolic volumes.22 Two other landmark studies, on the other hand, did not observe a significant improvement in LV function or dimensions at 4- to 6-month follow-up,23,24 although Janssens et al.23 observed a reduction in infarct size 4 months after intracoronary cell transfer in a study with very early BMC administration (i.e. within 24 h). Although definite reasons for these mixed results remain elusive, differences in study protocol and design, including time from reperfusion to cell injection, type, number, and isolation technique of cells, or follow-up design have been discussed. Whereas BMCs were infused within the first 7 post-infarct days in most trials, in Janssen's trial, cells were injected within the 24 h after AMI.23 In the ASTAMI trial, magnetic resonance imaging (MRI) was not performed until 2–3 weeks after cell transfer, whereas only echocardiography was done at baseline. Further, cells by contrast were prepared differently following the Lymphoprep technique.24 Subsequently, follow-up data on the REPAIR-AMI and BOOST collectives have become available. In REPAIR-AMI, the improvement of LV function was sustained after 12 months20 and was associated with a significant reduction in major adverse cardiovascular events after AMI over this period;25 an observation that carried on until 2 years of follow-up.26 Hence, in BOOST, the difference in LV-EF between the groups was no longer significant after 18 months,27 although an echocardiographic substudy revealed a persistent enhanced diastolic function from BMC application.28 Recently, 5-year follow-up data from the BOOST collective did not show a sustained benefit on systolic and diastolic LV function after a single BMC infusion.16 Interestingly, subgroup analyses suggested that patients with a more severely impaired LV function may have a benefit from BMC administration, whereas patients with a rather preserved LV function post-MI may not benefit.

In the controlled but non-randomized BALANCE study,29 haemodynamics, measures of LV function and geometry, contractility, infarct size, exercise capacity, and, of note, mortality remained improved up to 5 years after BMC infusion when compared with a matched, non-randomized control group. However, these results should be interpreted with caution, given the non-randomized design of the study. Another randomized study from China with a long-term follow-up has recently suggested that BMC administration may lead to an improved LVEF after 4 years.30 Notably, the results of the recently published REGENT trial are discussed below, because one study arm received selected CD34+/KDR+ BMCs.

Chronic myocardial infarction

In patients with CMI, less experience from clinical studies is available. The early-phase non-randomized IACT study by Strauer et al.31 suggested that intracoronary BMC transfer more than 5 months after MI may result in smaller infarct size, better LV-EF, and wall movement velocity associated with signs of higher cardiac metabolism in the infarcted myocardium. This application has been revisited by a carefully designed cross-over study where intracoronary BMC transfer more than 3 months after MI led to a significant improvement of LV-EF related to enhanced regional contractility in the area of cell application.32 Of note, this effect was also visible even in patients who crossed-over from control or treatment with circulating progenitor cells.32

Strauer et al.33 have recently reported the long-term follow-up data on the intracoronary application of BMCs in patients with chronic heart failure (CHF) due to ischaemic cardiomyopathy from the non-randomized STAR study. Over a 5-year follow-up, intracoronary BMC administration was not associated with adverse events. The authors reported an improved LV performance, quality of life, and survival in patients with CHF who agreed to BMC application when compared with the control group with a similar LV-EF, who did not agree to BMC treatment.33 However, due to the non-randomized design of the study, these results need to be interpreted with caution.

Refractory myocardial ischaemia

Another set of early-phase studies has addressed the effect of BMCs in patients with refractory myocardial ischaemia lacking options for revascularization. These studies jointly suggest that BM-derived cell injection via transepicardial (e.g. during bypass surgery) or transendocardial (e.g. guided via EEM) may improve subjective endpoints such as angina frequency or heart failure symptoms, and/or measures of global/regional wall motion and perfusion.34–38 In the randomized-controlled, double-blind trial conducted by van Ramshorst et al.,39 intramyocardial application of BMCs resulted in a modest but significant improvement of myocardial perfusion as assessed by SPECT, angina severity, and quality of life during a 3-month follow-up in patients with severe angina (classes III–IV), despite optimal medical therapy, ineligible for myocardial revascularization, and evidence of myocardial ischaemia at baseline. Similarly, 6 months after direct injection of autologous BMCs in patients with severe refractory angina, a significant improvement of exercise time, LV function, and NYHA functional class was observed in the PROTECT-CAD trial.40 The data of the ACT34-CMI trial in a similar patient population are discussed below.

Cumulatively, the studies discussed above suggest feasibility and some studies suggest efficacy of BMC-based therapy in acute/chronic MI as well as chronic refractory angina. Recent meta-analyses that summarized more than 1000 patients showed a significant improvement in LV-EF after BMC therapy on top off standard treatment.41–43 It needs to be acknowledged, however, that LV-EF might not have been the ideal endpoint to clearly detect efficacy (also see Endpoint selection). Overseeing safety data from up to 5 years, no sustained safety issues associated with the use of unselected BMCs have been observed after cardiac transplantation in clinical studies.

Circulating/mobilized CD133+ and CD34+ stem and progenitor cells

CD133 and CD34 are the most commonly used single markers for the enrichment of haematopoietic stem cells (HSCs). The observation that selection of certain cell populations, i.e. CD34+ cells from total mononuclear circulating cells, may augment their potency for cardiac repair has raised the interest in using selected cell populations as opposed to unselected BMCs.44 Baseline levels of circulating stem/progenitor cells are known to be low, which restricts their therapeutic use. To leverage their therapeutic potential, these cell types can be pharmaceutically mobilized from the BM into the circulation in order to be isolated and enriched (i.e. leukapheresis). Driven by the history of the field, EPCs, a potential progeny of HSCs, have been in the focus (for review see45,46).

CD133+ cells

CD133+ cells are more immature and less lineage-determined than CD34+ cells. Intracoronary infusion of selected CD133+ cells after recent AMI has been evaluated in a small-scale, non-randomized clinical study that revealed improved LV-EF paralleled by a reduction in myocardial perfusion defect after 4 months.47 However, more coronary events, such as stent occlusion and in-stent restenosis, were observed after CD133+ cell transfer. The authors further reported a time-dependent adverse remodelling of the infarct-related artery with accelerated luminal loss and a reduced conductance after CD133+ cell transfer.48 However, when CD133+ cells were injected locally during bypass surgery in patients with recent AMI, no safety concerns became evident in a small, non-randomized study, whereas regional wall motion was improved associated with better myocardial perfusion and viability.49 Transepicardial injection of CD133+ cells into the border zone of MI during operative revascularization in patients who had previous MI was reported by Stamm et al.50,51 in a small, uncontrolled study. Since no adverse events were reported, treatment was considered safe and feasible. The conclusion that this treatment resulted in improved LV function, however, is limited by the lack of a control group.50,51

CD34+ cells

CD34+ cells contain more endothelial lineage-determined cells than CD133+ cells and are therefore considered as a cell population enriched for ‘early‘ EPCs. In the randomized-controlled REGENT trial, unselected and CD34+/CXCR4+-selected BMCs were examined for their effects in LV function after MI in patients with reduced LV function (EF 40%).52 After 6 months, LV-EF increased by 3% in patients treated with unselected BMCs, 3% in patients receiving CD34+/CXCR4+-selected BMCs, and remained unchanged in the control group. There were, however, no significant differences in absolute changes of LV-EF between the groups.52 There was a trend in favour of BMC efficacy in individuals with most severely impaired LV dysfunction, as has been observed in several other studies using BMCs after acute MI.53 A potential limitation of this trial was that MRI measurements of LV function were only completed in a subgroup of patients.

We and others have evaluated intramyocardial injection of CD34+ progenitors in coronary artery disease (CAD) patients with chronic angina. Our Phase I/IIa pilot study suggested safety and feasibility as well as a positive trend of bioactivity as evidenced by SPECT perfusion imaging 6 months after CD34+ progenitor cells were injected into the hibernating myocardium in patients with refractory chronic angina; transendocardial delivery was guided by EMM (NOGA mapping) to identify ischaemic but still viable myocardium.54 These trends were further substantiated by our subsequent Phase IIb randomized-controlled, multicentre ACT34-CMI trial.55 In ongoing studies, this concept is under evaluation for patients critical limb ischaemia (clinicaltrials.gov: NCT00616980). So far, no safety issues are evident with the use of CD34+ cells. Whether further selection using the combination of different markers augments cellular repair capacity has to be determined in the future.

Mesenchymal stem cells

Mesenchymal stem cells or stromal cells constitute another potential option for stem/progenitor cell-based therapy, and their use is also evaluated as a potential allogeneic approach based on their immunomodulatory properties. Mesenchymal stem cells are stromal cells present in various tissues, such as BM and adipose tissue. Reflecting their paracrine activity, they exert anti-inflammatory and anti-apoptotic effects.56 Local immunosuppressive action has fuelled hope of an allogeneic MSC transplantation as an ‘of-the-shelf’ cell-based therapy to surround practical limitations of cell resources and ex vivo culture often required in the autologous setting.

The regenerative capacity of MSCs in general and the controversially discussed aspect of immune privilege57,58 of allogeneic MSCs needs to be evaluated in men. Autologous and allogeneic MSC transfer is currently under investigation; however, clinical data are scarce. In a randomized-controlled, double-blinded Phase I study, intravenous application of allogeneic MSCs after acute MI did not raise safety concerns and as assessed by a global symptom score might be efficacious over a period of 6 months.59 In early studies, MSCs were injected intravenously; however, the pulmonary passage of these large cells may be problematic.60 Since these positive efficacy data stand in contrast to negative experience from intravenous BMC applications, this set of data should still be considered with caution. Subsequently, intracoronary application of MSCs after AMI has been evaluated in two non-randomized early-phase studies by Chen et al. A high-dose of BM-derived MSCs (6 × 1010) resulted in a significant improvement of LV-EF in several modalities,61 whereas a lower dose (5 × 106) did not improve LV function in chronic ischaemic cardiomyopathy in a subsequent study by the same authors.62 Still, MSC treatment resulted in an improved exercise capability and heart failure symptomatology after 3 months.

Adipose tissue can also serve as a source of MSCs, i.e. adipose tissue-derived stem cells (ADSCs). Two clinical trials—APOLLO and PRECISE—are exploring the safety, feasibility, and efficacy of freshly isolated ADSCs with the Cellution™ system (Cytori Therapeutic Inc.) in patients with either AMI or CMI.

Cardiac-derived cardiovascular stem and progenitor cells

Until recently, our dogma was that the fully differentiated heart has no capability for cell turnover and self-repair. In their elegant observation, Bergmann et al.63 showed evidence for in-men cardiomyocyte renewal at a rate of 1% per year in younger adults and 0.5% in the elderly. In post-natal hearts, various subtypes of tissue-resident cardiac stem and progenitor cells (CSCs) classified by surface antigens and transcription markers have been reported, although it is undetermined whether these subtypes have clearly distinct phenotypes. Cardiac stem and progenitor cells, which have been suggested to be capable of creating cardiomyocytes and all surrounding cell types, are a promising candidate-at least in theory-to provide contractility and vascularization.64 In the light of the fact that their genuine number is low, CSCs isolated from endomyocardial biopsies have successfully been expanded ex vivo to leverage this therapeutic concept.65 Dr Marban's group has proposed a population of potential clinical relevance that has been identified by expanding CSCs from self-adherent clusters (cardiospheres) under certain conditions, i.e. cardiosphere-derived stem cells (CDCs).66,67 There is still some controversy on the cardiomyogenic potential of cardiospheres.68,69 Dr Field's group has recently suggested by using genetic cell tracking that there are temporal limitations for the ability of cardiac-resident c-kit+ cells to acquire a cardiomyogenic phenotype, i.e. that the cardiomyogenic population is present in neonatal hearts but largely lost in adult mouse hearts and suggested that elucidation of the underlying molecular mechanisms may permit a more robust cardiomyogenic induction in adult-derived cardiac c-kit+ cells.70

Early-stage clinical studies currently address safety and feasibility of cardiosphere-derived stem and progenitor cell transplantation. In the SCIPIO trial (clinicaltrials.gov: NCT00474461), patients with ischaemic cardiomyopathy from CMI who undergo bypass surgery received an intracoronary infusion of autologous CSCs isolated from their right atrial appendages. Further, patients with ischaemic LV dysfunction from recent MI receive an intracoronary injection of CDCs in the ongoing Phase I randomized dose-escalation CADUCEUS trial (clinicaltrials.gov: NCT0089336).

Skeletal myoblasts

The concept of resident stem cells (i.e. satellite cells), which are quiescent under normal conditions, contribute to new myocytes in response to injury is rather well established for skeletal musculature. Skeletal myoblasts can be conveniently isolated from muscle biopsies and ex vivo expanded for therapeutic use. After pre-clinical evidence showed their repair effects in ischaemic myocardium,71,72 SMs have been thought to transdifferentiate into cardiomyocytes. In the meanwhile, pre-clinical data indicate that SMs maintain a skeletal muscle fate,73 infrequently fuse with cardiomyocytes,74 and hardly couple electromechanically with the host myocardium.75

The clinical value of SMs is uncertain. Initially, several uncontrolled early-phase studies generated promising results for the therapeutic utility of SMs in CHF, suggesting an improved global and regional contractility and/or viability in the infarct zone. In most studies, SMs were overly injected via a transepicardial route during graft surgery,76–78 whereas only one study reported the transendocardial injection of myoblasts as safe and feasible.79 The most comprehensive clinical evaluation of SMs, so far, has been the multicentre, randomized-controlled, double-blind Phase II MAGIC trial.80 Herein, autologous, for 3 weeks ex vivo expanded SMs were directly administered around the scar tissue in patients with ischaemic cardiomyopathy who underwent bypass surgery. After 6 months, primary endpoints, namely global and regional LV function assessed by echocardiography, were not significantly changed. Notably, the authors reported a significant reduction in LV volumes in the high-dose group. The longest clinical experience with SM transfer, however, has been published by Dib et al. In their non-randomized, uncontrolled Phase I study, patients undergoing surgery for revascularization or implantable cardioverter-defibrillator implantation showed an increase in LV-EF and viability, whereas no adverse events were observed up to 4 years transepicardial injection of autologous SMs.81

Fuelled by an earlier report from Menasche et al.76 where the use of myoblasts was associated with arrhythmic events in 40% of the patients, SMs have been considered to be pro-arrhythmogenic. In the subsequent MAGIC trial, no significant increase in arrhythmic events was reported, although it must be acknowledged that there was a trend towards more arrhythmias in SM-treated patients despite treatment with amiodarone a priori.80 Hence, none of the other early phase above nor the 4-year surveillance by Dib et al.81 has added evidence for SM-induced sudden death. Chachques et al. hypothesized that the arrhythmicity of SMs may be conditioned by the bovine serum used during ex vivo expansion for 3 weeks (cellular cardiomyoplasty) that may constitute an antigenic and thereby inflammatory substrate. A strictly autologous preparation using the corresponding donor serum in this rather small-sampled study did not lead to any arrhythmias over 1–2 years of follow-up.82 As the majority of the above-mentioned, early-phase studies did not report arrhythmic events, it remains vague whether this particular procedure stabilizes SMs electrically. There is still debate about the potential pro-arrhythmicity of different adult stem/progenitor cells, in particular the SMs.83,84 Further, in contrast to earlier hesitations to infuse SMs intracoronary in the light of a potential risk for microembolization due to their cell size, there were no adverse events following transcoronary-venous SMs delivery observed in the POZNAN trial.85 The potential risk of arrhythmias and sudden death needs, however, ultimate clarification for this cell type.

Endogenous mobilization of stem/progenitor cells

In contrast to exogenous cell transfer requiring invasive delivery, adult stem/progenitor cells can be mobilized from the BM by systemic administration of certain cytokines [e.g. granulocyte colony-stimulating factor (G-CSF)] to augment circulating levels of these cells and, thereby, enhance ischaemic tissue repair via circulating stem/progenitor cells. This concept has been transferred from the haematologists who isolate HSCs from the bloodstream before ablation of the BM in stem cell transplantation.

Earlier, the authors of the much debated MAGIC trial reported that G-CSF mobilization after MI was associated with an unexpected higher rate of in-stent restenosis at the culprit lesion, whereas intracoronary infusion of peripheral blood stem cells appeared safe and potentially efficacious; because of this safety issue, the study was discontinued.86 Subsequently, in a controlled, non-randomized study by Ince et al.,87 G-CSF mobilization of CD34+ BMCs shortly after angioplasty in AMI improved LV function and metabolic activity and attenuated LV remodelling up to 12 months without accentuation of the restenosis rate or late adverse events. In the same line, Valgimigli et al.88 showed an unremarkable safety profile for G-CSF in patients with AMI, although LV perfusion or function was unchanged 6 months after treatment. Furthermore, G-CSF did not improve LV wall motion or perfusion over the period of 1 month in patients with stable CAD.89 Of note, there was a trend towards more ischaemia, and in 2 out of 16 patients reinfarction occurred.89 Early clinical experience with stem cell mobilization by G-CSF from 10 trials, including 445 patients with AMI, was recently summarized in a meta-analysis by Zohlnhöfer et al. Herein, the authors concluded that cumulatively the data do not support efficacy of endogenous stem cell mobilization by G-CSF.90 Without evidence for efficacy on the one side, and a potentially questionable safety profile on the other (i.e. with respect to restenosis), large-scale trials, which would be needed to clarify the clinical potential, could not be advocated. Interestingly, very early G-CSF administration (<12 h) has recently been reported to attenuate ventricular remodelling after large, anterior MI, whereas systolic function and myocardial perfusion were unchanged in the STEM-AMI collective.91

In recent years, pharmaceutical compounds emerged to modulate well-defined cascades of stem/progenitor cell biology and homing. Continuing the concept of endogenous stem cell mobilization, Zaruba et al.92 proposed a combined strategy of G-CSF with dipeptidylpeptidase IV (DPP-IV) inhibition to improve cardiac homing of mobilized stem/progenitor cells, which is currently under clinical investigation in the SITAGRAMI trial in patients after AMI. This concept proposes that inhibition of DPP-IV that is cleaving one of the main stem cell attracting chemokines, SDF-1α, will improve homing of mobilized stem/progenitor cells. More recent results from our group and others described the CXCL12/CXCR4 axis, the SDF-1α pathway, as a relevant regulator of endogenous cell mobilization.93 In pre-clinical studies, the CXCR4-antagonists Plerixafor (known as Mobozil or AMD3100) mobilizes stem/progenitor cells from the BM, increases BM-derived cell incorporation in the ischaemic border zone, and improves cardiac function post-MI.93 Because this agonist has clinically been used as HIV therapeutic without relevant side effects for years, its safety profile appears favourable. To our knowledge, no clinical data are available on any of these pharmaceutical strategies to therapeutically modulate endogenous stem/progenitor cell trafficking.

Emerging stem cell types with a potential for cardiomyogenic differentiation

Embryonic stem cells

Embryonic stem cells (ESCs) posses several features that are conceptually attractive for cardiac repair. Embryonic stem cells are pluripotent, which means that they have the ability to differentiate into all cell lineages.94,95 On the other hand, there are substantial ethical and regulatory concerns with their retrieval. The limited availability further hinders its therapeutic utility. In addition, there is a risk for malignancies (i.e. intra- and extracardiac teratoma or other tumour formation) associated with the use of ESCs,96,97 as it has recently become evident in a patient who developed a likely donor-derived multifocal brain tumour after treatment with foetal neural stem cells.97 At the same time, reliable modalities to regulate and control differentiation in a targeted and controllable fashion are challenging, although several approaches to limit tumour formation have been explored, including strategies to enhance cardiopoietic programming of ESCs.98

Furthermore, following allogeneic application, ESCs may trigger an immune response in the recipient. Finally, it remains elusive whether human ESCs efficiently structurally engraft and electromechanically integrate into ischaemic myocardium. The above-described limitations are some of the hurdles that currently hinder the transition of ESC-based therapy into clinical translation.

Inducible pluripotent cells

In 2006, Takahashi and Yamanaka99 reported that differentiated murine fibroblasts could be reprogrammed into stem cells with the capacity to form all three germ layers and termed these cells induced pluripotent stem cells (iPS). Nuclear reprogramming with ectopic stemness factors has opened the opportunity to generate autologous patient-derived iPS from adult somatic cells.99,100 The ability of both mouse and human iPS to differentiate in functional cardiomyocytes has recently been demonstrated.101,102

The study of iPS from selected cohorts of patients is an innovative way to uncover molecular mechanisms of disease, such as nicely illustrated in the study of Moretti et al.,103 who generated pluripotent stem cells from dermal fibroblasts of patients with long-QT syndrome type-1 and subsequently induced their differentiation into functional cardiac myocytes that recapitulated the electrophysiological features of the disorder.104

Functionally, intramyocardially injected undifferentiated iPS, but not parental fibroblasts, engrafted and improved contractile function of infarcted myocardium while attenuating adverse remodelling in immunocompetent mice.105 Only in immunocompetent mice, the environment after cardiac transplantation was permissive for differentiation, whereas in immunodeficient mice, tumour development was observed, which highlights the importance of immune surveillance to prevent tumour growth.105 New technologies such as small molecule screen and epigenetic modifications most probably will establish further potentially more safe options for the generation of iPS. It will, however, be crucial to validate the epigenetic and phenotypic stability in the reprogrammed state. Also, reprogramming pluripotency in somatic cells comes with the risk of tumorigenicity as described above. Furthermore, iPS become immunologically relevant while they differentiate with up-regulation of histocompatibility antigens. This aspect would narrow the range of applications to the autologous setting.106 As described above, several important hurdles have to be resolved before a clinical translation of iPS-based therapies can be considered, including safety issues to prevent tumour growth that may require determination of the appropriate differentiation of iPS-derived cells and removal of residual undifferentiated cells before transplantation.107 In addition, upscaling for an effective iPS-based cell generation will be required. Several important considerations in the proposed mechanisms of cell-based therapy for cardiac repair and its further development are described in the Supplementary material online and depicted in Figures 3–5.

Figure 3

Proposed mechanisms of ischaemic tissue repair via stem and progenitor cell-based therapies.

Figure 3

Proposed mechanisms of ischaemic tissue repair via stem and progenitor cell-based therapies.

Figure 4

Open questions for the optimization of the therapeutic efficacy of stem and progenitor cells.

Figure 4

Open questions for the optimization of the therapeutic efficacy of stem and progenitor cells.

Figure 5

Combined Strategies of biological cardiac repair.

Figure 5

Combined Strategies of biological cardiac repair.

Future directions of cell-based therapy: a roadmap

Various strategies have been proposed to support stem cells in the hostile environment of ischaemic tissue characterized by ischaemia, acidosis, inflammation, and oxidative stress. Beyond the modulation of cell homing, viability, engraftment, and retention, it becomes more and more clear that true repair of damaged myocardium will need more than a single-dose administration of cells.

Priming of stem and progenitor cells to enhance their therapeutic efficacy

The concept to pre-treat or modify stem/progenitor cells before application (priming) and thereby enhance their therapeutic potency has evolved from earlier pre-clinical observations.108–114 These strategies basically target any function step that influences cell fate from the application on: adhesion/transmigration, homing, migration, engraftment, survival, cell–cell interaction, repair capacity, differentiation, and retention. Potential tools for modification include drugs, small molecules, naked and vector-facilitated plasmids, and epigenetic reprogramming (for more details see115,116). Priming of dysfunctional autologous cells from cardiovascular patients via any of these tools may allow for a ‘resetting of impaired biopotency’.

Among multiple targets stemming from pre-clinical evaluation, the following examples are under clinical investigation: we and others have identified a reduced endothelial NO synthase-dependent NO production as an important mechanism limiting the functional repair capacity of endogenous progenitor cells in patients with diabetes or hypertension.108,117 In the randomized, placebo-controlled ENACT-AMI trial, the therapeutic use of eNOS-overexpressing EPCs is presently studied in patients with large MI (clinicaltrials.gov: NCT00936819).118 As another example of modified stem/progenitor cells, in the MESAMI II trial (clinicaltrials.gov: registration in process) designed by Roncalli and colleagues, patients with no-option chronic ischaemic cardiomyopathy will receive an intramyocardial injection of MSCs pre-treated with melatonin. This concept is based on pre-clinical data showing that pre-treatment with the pineal hormone increases survival, paracrine activity, and therapeutic efficiency of MSCs in a rodent ischaemia model.119 Another way to boost paracrine and differential cell functions is to pre-stimulate cells before application.120,121 This concept is currently translated into patients with heart failure from ischaemic cardiomyopathy by pre-incubation of BM-derived MSCs with growth factors to guide their transition into cardiopoietic cells (C-Cure trial, clinicaltrials.gov: NCT00810238).

As no clinical study of primed stem cells has been completed yet, it is going to be interesting whether these strategies will hold promise in clinical applications. Many more targeted cell modifications can be expected to be in transition from bench to bedside at present.

Bionanotechnology to support cell-based therapies

In addition to the harmful biochemical milieu, loss of tissue architecture and loss of matrix support within the infarcted myocardium detrimentally affect cell–cell and cell–matrix interaction and, in turn, regulation of dependent pathways that are functionally inevitable for the homeostasis of transplanted cells. The rapidly evolving field of bionanotechnology allows to specifically design biomaterials to support transplanted cells within this ischaemic environment.122 Herein, the structure, dimensions, and shape of constructs are pivotal to better mimic the native architecture of extracellular matrix. An optimal biomaterial to support cell therapy should provide a three-dimensional environment to enhance biomechanical properties of extracellular matrix; a purpose for which controlled organization at nano-scale is needed (for more details see123). In some biomatrices, bioactive signals can be incorporated to specifically modulate stem cell biology while supporting them structurally.124

The strategy to support cell transfer has rapidly gained attention triggered by exciting pre-clinical data. In murine models, nanofibres that self-assemble into a matrix recruited endogenous progenitors to the myocardium and supported transplantation of cardiomyocytes providing a microenvironment.125 In principle, biomaterials can be custom-designed to optimally fit the organ-specific microenvironment.126 Furthermore, bioactive signals can be incorporated in some biomaterials to additionally enhance cell survival, retention, proliferation, and differentiation. In this context, Padin-Iruegas et al.127 reported that an insulin-like growth factor carrying nanofibre enhances CSC-dependent repair of cardiac injury.128 In our hands, the combination of a linage-specific optimized, self-assembling nanofibre enhances the potency of cell-therapy in ischaemic tissue repair.129 Also, bioactive sequences of biologically attractive paracrine factors, e.g. SDF-1, can more effectively be presented via biomaterials with the aim to recruit endogenous into or support exogenously applied cells in ischaemic myocardium.130

Although emerging results for the role of bionanomaterials in cell-based ischaemic tissue repair are promising, there has not been precedence in humans. Before any clinical translation, several aspects such as dosing, dynamics and kinetics of bioactivity, biodegradability, occurrence and excretion of breakdown products, and immune compatibility have to be carefully addressed.

Tissue engineering

Tissue engineering has now been advanced for several years. In particular aiming at replacement of the myocardium, the breakthrough in this field has been hindered by several challenges. While cell seeding of construct backbones has worked well for proliferative and hypoxia-tolerant cells, it has been difficult to achieve tissue-like densities with cells with low proliferation rate such as cardiomyocytes,122 although successful generation and transplantation of engineered heart tissue grafts has been reported in small animal models.131 Achieving sufficient perfusion of larger constructs is challenging. Passive diffusion is generally tolerated up to a distance of <0.1–0.2 mm. In the case of longer distances, dysfunctionality and necrosis occur as a failure of sufficient diffusion.132 At present, bigger, more complex constructs such as myocardium (1.0–1.5 cm) cannot be maintained by simple diffusion and need anastomosis to a vascular network. Since generation of a stable and functional construct microenvironment remains critical, stem and progenitor cells display a strong potential to accelerate tissue engineering for the purpose of seeding but also for the creation of a vascular networks.133

Combined strategies of biological repair

As stated above, single-dose transfer of a single cell type into a deranged environment will likely not be sufficient to ‘regenerate’ a complex tissue such as the heart. More recent insights suggest that combined strategies of biological repair more closely resemble native biological mechanisms and, thus, may be more potent than current one-stop, single-cell strategies (Figure 5). Conceptually, the combination of different types of stem/progenitor cells with stromal cells is functionally very attractive aiming at synergisms. Different cell (sub-) populations may exert different regenerative effects. Unselected and selected cells, for example, showed different spatial patterns of homing.15 Melero-Martin et al.133 recently described striking evidence for the synergistic interaction of EPCs and MSCs, which contain relevant pericytes, to create a substantial and functional vascular network in a Matrigel assay that was stable for up to 4 weeks.

To add yet another level of complexity, supplemental tools that are aimed to improve efficacy of cell transfer have become available. Engraftment of cardiac-derived stem cells (CSCs) after intramyocardial application, for example, is improved after sealing the injection site with fibrin glue to attenuate the known leakage of cell suspension.134 Low-energy shock wave treatment of the target tissue has been shown to enhance recruitment of circulating EPCs by enhancing local expression of chemoattracting growth factors in mice.135 This technology is thought to prepare the ischaemic target zone for cell transfer and thereby indirectly augment cell homing and retention. In the ongoing Cellwave study (clinicaltrials.gov: NCT00326989), extracorporal shock wave pre-treatment before intracoronary application of BM-derived progenitor cells is already under clinical evaluation in patients with CMI. In addition, homing of cells via the intracoronary route can be improved by disrupting cell-carrying microbubbles via ultrasound. Without evoking undesired damage, this technology appears to facilitate vascular transmigration by creating capillary pores.136,137

With all limitations and shortcomings in mind, the idea to realize effective cardiac tissue repair by using only one cell type is likely challenging. Depending on further mechanistic and clinical insights, we envision combined, precisely timed, multi-step approaches that incorporate various stem and stromal cells, paracrine factors, and specifically bioengineered tools for the future cardiac regenerative medicine in order to advance this exciting field to the next level, the level of true ischaemic tissue repair.

Summary

We are currently in the phase of translation of cardiac cell-based therapy, and good translation without any surprise takes time and efforts. After the initial hype revolving cell-based cardiac tissue repair led to a rather rapid translation into early-phase clinical trials, we have now reached the stage where conclusive answers and thoughtful fine-tuning, which includes a step back to the bench to find answers, are needed. There is some consensus that cell-based therapy has potential beneficial effects on top of standard medial therapy as it has been expressed by the task force of European Society of Cardiology.138 Apart from uncertainties and limitations discussed above, several pressing tasks need to be addressed: sustained efficacy needs to be proven for each cell type depending on the treated entity. Comparative studies may allow discriminating superior cell populations, sources, timing, dosing, and delivery mode considering with regard to certain applications. Safety profiles dependent on cell type, delivery route, and underlying disease need to be characterized by long-term follow-up of larger collectives. To substantiate these aspects, large-scale, multicentre trials are clearly needed. In order to predict benefit, influencing factors need to be identified with the aim to focus resources and efforts. Local retention and fate of cells in the therapeutic target zone must be improved. Further understanding of regenerative mechanisms will enable optimization at all levels. Cell priming, bionanotechnology, and tissue engineering are emerging tools and may merge into a combined biological approach of ischaemic tissue repair.

After a hectic decade, it is time to catch breath and focus efforts on concise pre-clinical work, and thoughtfully designed, sufficiently powered clinical trials to find answers to important remaining questions, to clarify on uncertainties, and to overcome limitations with the aim to optimize cell-based therapy. Despite all promise, eventually, we are challenged to show robust effects on disease progression, morbidity, and mortality associated with an acceptable safety profile to advance the promising concept of cell-based therapy to clinical routine.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

J.T. was supported by the American Heart Association (Midwest Affiliate), the German Heart Foundation, and Solvay Pharmaceuticals. D.W.L. was supported by NIH grants R01 HL53354, R01 HL77428, R01 HL80137, and R01 HL95874. U.L. was supported by Swiss National Research Foundation grants 310030-122339 and 33CM30-124112/1 and the Zurich Center of Integrated Human Physiology.

Conflict of interest: none declared.

References

1
Fang
J
Mensah
GA
Croft
JB
Keenan
NL
Heart failure-related hospitalization in the U.S., 1979 to 2004
J Am Coll Cardiol
 , 
2008
, vol. 
52
 (pg. 
428
-
434
)
2
Gheorghiade
M
Bonow
RO
Chronic heart failure in the United States: a manifestation of coronary artery disease
Circulation
 , 
1998
, vol. 
97
 (pg. 
282
-
289
)
3
Asahara
T
Murohara
T
Sullivan
A
Silver
M
van der Zee
R
Li
T
Witzenbichler
B
Schatteman
G
Isner
JM
Isolation of putative progenitor endothelial cells for angiogenesis
Science
 , 
1997
, vol. 
275
 (pg. 
964
-
967
)
4
Hirschi
KK
Ingram
DA
Yoder
MC
Assessing identity, phenotype, and fate of endothelial progenitor cells
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
1584
-
1595
)
5
Aicher
A
Zeiher
AM
Dimmeler
S
Mobilizing endothelial progenitor cells
Hypertension
 , 
2005
, vol. 
45
 (pg. 
321
-
325
)
6
Hristov
M
Erl
W
Weber
PC
Endothelial progenitor cells: mobilization, differentiation, and homing
Arterioscler Thromb Vasc Biol
 , 
2003
, vol. 
23
 (pg. 
1185
-
1189
)
7
Dimmeler
S
Regulation of bone marrow-derived vascular progenitor cell mobilization and maintenance
Arterioscler Thromb Vasc Biol
 , 
2010
, vol. 
30
 (pg. 
1088
-
1093
)
8
Yi
BA
Wernet
O
Chien
KR
Pregenerative medicine: developmental paradigms in the biology of cardiovascular regeneration
J Clin Invest
 , 
2010
, vol. 
120
 (pg. 
20
-
28
)
9
Segers
VF
Lee
RT
Stem-cell therapy for cardiac disease
Nature
 , 
2008
, vol. 
451
 (pg. 
937
-
942
)
10
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
, vol. 
106
 (pg. 
1913
-
1918
)
11
Frangogiannis
NG
Smith
CW
Entman
ML
The inflammatory response in myocardial infarction
Cardiovasc Res
 , 
2002
, vol. 
53
 (pg. 
31
-
47
)
12
Schachinger
V
Aicher
A
Dobert
N
Rover
R
Diener
J
Fichtlscherer
S
Assmus
B
Seeger
FH
Menzel
C
Brenner
W
Dimmeler
S
Zeiher
AM
Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium
Circulation
 , 
2008
, vol. 
118
 (pg. 
1425
-
1432
)
13
Barbash
IM
Chouraqui
P
Baron
J
Feinberg
MS
Etzion
S
Tessone
A
Miller
L
Guetta
E
Zipori
D
Kedes
LH
Kloner
RA
Leor
J
Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution
Circulation
 , 
2003
, vol. 
108
 (pg. 
863
-
868
)
14
Aicher
A
Brenner
W
Zuhayra
M
Badorff
C
Massoudi
S
Assmus
B
Eckey
T
Henze
E
Zeiher
AM
Dimmeler
S
Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling
Circulation
 , 
2003
, vol. 
107
 (pg. 
2134
-
2139
)
15
Hofmann
M
Wollert
KC
Meyer
GP
Menke
A
Arseniev
L
Hertenstein
B
Ganser
A
Knapp
WH
Drexler
H
Monitoring of bone marrow cell homing into the infarcted human myocardium
Circulation
 , 
2005
, vol. 
111
 (pg. 
2198
-
2202
)
16
Meyer
GP
Wollert
KC
Lotz
J
Pirr
J
Rager
U
Lippolt
P
Hahn
A
Fichtner
S
Schaefer
A
Arseniev
L
Ganser
A
Drexler
H
Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
2978
-
2984
)
17
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
, vol. 
95
 (pg. 
742
-
748
)
18
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
, vol. 
106
 (pg. 
3009
-
3017
)
19
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
, vol. 
44
 (pg. 
1690
-
1699
)
20
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
, vol. 
355
 (pg. 
1210
-
1221
)
21
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
, vol. 
364
 (pg. 
141
-
148
)
22
Schachinger
V
Assmus
B
Erbs
S
Elsasser
A
Haberbosch
W
Hambrecht
R
Yu
J
Corti
R
Mathey
DG
Hamm
CW
Tonn
T
Dimmeler
S
Zeiher
AM
Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial
Eur J Heart Fail
 , 
2009
, vol. 
11
 (pg. 
973
-
979
)
23
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
, vol. 
367
 (pg. 
113
-
121
)
24
Lunde
K
Solheim
S
Aakhus
S
Arnesen
H
Abdelnoor
M
Egeland
T
Endresen
K
Ilebekk
A
Mangschau
A
Fjeld
JG
Smith
HJ
Taraldsrud
E
Grogaard
HK
Bjornerheim
R
Brekke
M
Muller
C
Hopp
E
Ragnarsson
A
Brinchmann
JE
Forfang
K
Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
1199
-
1209
)
25
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
, vol. 
27
 (pg. 
2775
-
2783
)
26
Assmus
B
Rolf
A
Erbs
S
Elsasser
A
Haberbosch
W
Hambrecht
R
Tillmanns
H
Yu
J
Corti
R
Mathey
DG
Hamm
CW
Suselbeck
T
Tonn
T
Dimmeler
S
Dill
T
Zeiher
AM
Schachinger
V
Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction
Circ Heart Fail
 , 
2010
, vol. 
3
 (pg. 
89
-
96
)
27
Meyer
GP
Wollert
KC
Lotz
J
Steffens
J
Lippolt
P
Fichtner
S
Hecker
H
Schaefer
A
Arseniev
L
Hertenstein
B
Ganser
A
Drexler
H
Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial
Circulation
 , 
2006
, vol. 
113
 (pg. 
1287
-
1294
)
28
Schaefer
A
Meyer
GP
Fuchs
M
Klein
G
Kaplan
M
Wollert
KC
Drexler
H
Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
929
-
935
)
29
Yousef
M
Schannwell
CM
Kostering
M
Zeus
T
Brehm
M
Strauer
BE
The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction
J Am Coll Cardiol
 , 
2009
, vol. 
53
 (pg. 
2262
-
2269
)
30
Cao
F
Sun
D
Li
C
Narsinh
K
Zhao
L
Li
X
Feng
X
Zhang
J
Duan
Y
Wang
J
Liu
D
Wang
H
Long-term myocardial functional improvement after autologous bone marrow mononuclear cells transplantation in patients with ST-segment elevation myocardial infarction: 4 years follow-up
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
1986
-
1994
)
31
Strauer
BE
Brehm
M
Zeus
T
Bartsch
T
Schannwell
C
Antke
C
Sorg
RV
Kogler
G
Wernet
P
Muller
HW
Kostering
M
Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study
J Am Coll Cardiol
 , 
2005
, vol. 
46
 (pg. 
1651
-
1658
)
32
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
, vol. 
355
 (pg. 
1222
-
1232
)
33
Strauer
BE
Yousef
M
Schannwell
CM
The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heart failure: the STAR-heart study
Eur J Heart Fail
 , 
2010
, vol. 
12
 (pg. 
721
-
729
)
34
Hamano
K
Nishida
M
Hirata
K
Mikamo
A
Li
TS
Harada
M
Miura
T
Matsuzaki
M
Esato
K
Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results
Jpn Circ J
 , 
2001
, vol. 
65
 (pg. 
845
-
847
)
35
Tse
HF
Kwong
YL
Chan
JK
Lo
G
Ho
CL
Lau
CP
Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation
Lancet
 , 
2003
, vol. 
361
 (pg. 
47
-
49
)
36
Fuchs
S
Satler
LF
Kornowski
R
Okubagzi
P
Weisz
G
Baffour
R
Waksman
R
Weissman
NJ
Cerqueira
M
Leon
MB
Epstein
SE
Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study
J Am Coll Cardiol
 , 
2003
, vol. 
41
 (pg. 
1721
-
1724
)
37
Perin
EC
Dohmann
HF
Borojevic
R
Silva
SA
Sousa
AL
Mesquita
CT
Rossi
MI
Carvalho
AC
Dutra
HS
Dohmann
HJ
Silva
GV
Belem
L
Vivacqua
R
Rangel
FO
Esporcatte
R
Geng
YJ
Vaughn
WK
Assad
JA
Mesquita
ET
Willerson
JT
Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure
Circulation
 , 
2003
, vol. 
107
 (pg. 
2294
-
2302
)
38
Perin
EC
Dohmann
HF
Borojevic
R
Silva
SA
Sousa
AL
Silva
GV
Mesquita
CT
Belem
L
Vaughn
WK
Rangel
FO
Assad
JA
Carvalho
AC
Branco
RV
Rossi
MI
Dohmann
HJ
Willerson
JT
Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy
Circulation
 , 
2004
, vol. 
110
 (pg. 
II213
-
II218
)
39
van Ramshorst
J
Bax
JJ
Beeres
SL
Dibbets-Schneider
P
Roes
SD
Stokkel
MP
de Roos
A
Fibbe
WE
Zwaginga
JJ
Boersma
E
Schalij
MJ
Atsma
DE
Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial
JAMA
 , 
2009
, vol. 
301
 (pg. 
1997
-
2004
)
40
Tse
HF
Thambar
S
Kwong
YL
Rowlings
P
Bellamy
G
McCrohon
J
Thomas
P
Bastian
B
Chan
JK
Lo
G
Ho
CL
Chan
WS
Kwong
RY
Parker
A
Hauser
TH
Chan
J
Fong
DY
Lau
CP
Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
2998
-
3005
)
41
Abdel-Latif
A
Bolli
R
Tleyjeh
IM
Montori
VM
Perin
EC
Hornung
CA
Zuba-Surma
EK
Al-Mallah
M
Dawn
B
Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis
Arch Intern Med
 , 
2007
, vol. 
167
 (pg. 
989
-
997
)
42
Lipinski
MJ
Biondi-Zoccai
GG
Abbate
A
Khianey
R
Sheiban
I
Bartunek
J
Vanderheyden
M
Kim
HS
Kang
HJ
Strauer
BE
Vetrovec
GW
Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
1761
-
1767
)
43
Martin-Rendon
E
Brunskill
SJ
Hyde
CJ
Stanworth
SJ
Mathur
A
Watt
SM
Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
1807
-
1818
)
44
Kawamoto
A
Iwasaki
H
Kusano
K
Murayama
T
Oyamada
A
Silver
M
Hulbert
C
Gavin
M
Hanley
A
Ma
H
Kearney
M
Zak
V
Asahara
T
Losordo
DW
CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells
Circulation
 , 
2006
, vol. 
114
 (pg. 
2163
-
2169
)
45
Besler
C
Doerries
C
Giannotti
G
Lüscher
TF
Landmesser
U
Pharmacological approaches to improve endothelial repair mechanisms
Expert Rev Cardiovasc Ther
 , 
2008
, vol. 
6
 (pg. 
1071
-
1082
)
46
Urbich
C
Dimmeler
S
Endothelial progenitor cells: characterization and role in vascular biology
Circ Res
 , 
2004
, vol. 
95
 (pg. 
343
-
353
)
47
Bartunek
J
Vanderheyden
M
Vandekerckhove
B
Mansour
S
De Bruyne
B
De Bondt
P
Van Haute
I
Lootens
N
Heyndrickx
G
Wijns
W
Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety
Circulation
 , 
2005
, vol. 
112
 (pg. 
I178
-
I183
)
48
Vanderheyden
M
Vercauteren
S
Mansour
S
Delrue
L
Vandekerckhove
B
Heyndrickx
GR
Van Haute
I
De Bruyne
B
Timmermans
F
Wijns
W
Bartunek
J
Time-dependent effects on coronary remodeling and epicardial conductance after intracoronary injection of enriched hematopoietic bone marrow stem cells in patients with previous myocardial infarction
Cell Transplant
 , 
2007
, vol. 
16
 (pg. 
919
-
925
)
49
Ahmadi
H
Baharvand
H
Ashtiani
SK
Soleimani
M
Sadeghian
H
Ardekani
JM
Mehrjerdi
NZ
Kouhkan
A
Namiri
M
Madani-Civi
M
Fattahi
F
Shahverdi
A
Dizaji
AV
Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction
Curr Neurovasc Res
 , 
2007
, vol. 
4
 (pg. 
153
-
160
)
50
Stamm
C
Westphal
B
Kleine
HD
Petzsch
M
Kittner
C
Klinge
H
Schumichen
C
Nienaber
CA
Freund
M
Steinhoff
G
Autologous bone-marrow stem-cell transplantation for myocardial regeneration
Lancet
 , 
2003
, vol. 
361
 (pg. 
45
-
46
)
51
Stamm
C
Kleine
HD
Westphal
B
Petzsch
M
Kittner
C
Nienaber
CA
Freund
M
Steinhoff
G
CABG and bone marrow stem cell transplantation after myocardial infarction
Thorac Cardiovasc Surg
 , 
2004
, vol. 
52
 (pg. 
152
-
158
)
52
Tendera
M
Wojakowski
W
Ruzyllo
W
Chojnowska
L
Kepka
C
Tracz
W
Musialek
P
Piwowarska
W
Nessler
J
Buszman
P
Grajek
S
Breborowicz
P
Majka
M
Ratajczak
MZ
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
 , 
2009
, vol. 
30
 (pg. 
1313
-
1321
)
53
Landmesser
U
Bone marrow cell therapy after myocardial infarction. What should we select?
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
1310
-
1312
)
54
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
, vol. 
115
 (pg. 
3165
-
3172
)
55
Losordo
DW
Henry
T
Schatz
RA
Lee
JS
Costa
M
Bass
T
Schaer
G
Niederman
A
Mendelsohn
F
Davidson
C
Waksman
R
Soukas
PA
Simon
D
Chronos
N
Fortuin
FD
Huang
PP
Weintraub
N
Yeung
A
Rosenfield
K
Wong
SC
Taussig
A
Rava
AN
Sherman
W
Kereiakes
D
Strumpf
RK
Port
S
Pieper
K
Adams
PX
Harrington
R
Abstract 5638: Autologous CD34+ cell therapy for refractory angina: 12 month results of the phase II ACT34-CMI study
Circulation
 , 
2009
, vol. 
120
 pg. 
S1132-a-
 
56
Pittenger
MF
Martin
BJ
Mesenchymal stem cells and their potential as cardiac therapeutics
Circ Res
 , 
2004
, vol. 
95
 (pg. 
9
-
20
)
57
Amado
LC
Saliaris
AP
Schuleri
KH
St John
M
Xie
JS
Cattaneo
S
Durand
DJ
Fitton
T
Kuang
JQ
Stewart
G
Lehrke
S
Baumgartner
WW
Martin
BJ
Heldman
AW
Hare
JM
Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction
Proc Natl Acad Sci USA
 , 
2005
, vol. 
102
 (pg. 
11474
-
11479
)
58
Poncelet
AJ
Vercruysse
J
Saliez
A
Gianello
P
Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo
Transplantation
 , 
2007
, vol. 
83
 (pg. 
783
-
790
)
59
Hare
JM
Traverse
JH
Henry
TD
Dib
N
Strumpf
RK
Schulman
SP
Gerstenblith
G
DeMaria
AN
Denktas
AE
Gammon
RS
Hermiller
JB
Jr.
Reisman
MA
Schaer
GL
Sherman
W
A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
2277
-
2286
)
60
Fischer
UM
Harting
MT
Jimenez
F
Monzon-Posadas
WO
Xue
H
Savitz
SI
Laine
GA
Cox
CS
Jr.
Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect
Stem Cells Dev
 , 
2009
, vol. 
18
 (pg. 
683
-
692
)
61
Chen
SL
Fang
WW
Ye
F
Liu
YH
Qian
J
Shan
SJ
Zhang
JJ
Chunhua
RZ
Liao
LM
Lin
S
Sun
JP
Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction
Am J Cardiol
 , 
2004
, vol. 
94
 (pg. 
92
-
95
)
62
Chen
S
Liu
Z
Tian
N
Zhang
J
Yei
F
Duan
B
Zhu
Z
Lin
S
Kwan
TW
Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery
J Invasive Cardiol
 , 
2006
, vol. 
18
 (pg. 
552
-
556
)
63
Bergmann
O
Bhardwaj
RD
Bernard
S
Zdunek
S
Barnabe-Heider
F
Walsh
S
Zupicich
J
Alkass
K
Buchholz
BA
Druid
H
Jovinge
S
Frisen
J
Evidence for cardiomyocyte renewal in humans
Science
 , 
2009
, vol. 
324
 (pg. 
98
-
102
)
64
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
, vol. 
114
 (pg. 
763
-
776
)
65
Bearzi
C
Rota
M
Hosoda
T
Tillmanns
J
Nascimbene
A
De Angelis
A
Yasuzawa-Amano
S
Trofimova
I
Siggins
RW
Lecapitaine
N
Cascapera
S
Beltrami
AP
D'Alessandro
DA
Zias
E
Quaini
F
Urbanek
K
Michler
RE
Bolli
R
Kajstura
J
Leri
A
Anversa
P
Human cardiac stem cells
Proc Natl Acad Sci USA
 , 
2007
, vol. 
104
 (pg. 
14068
-
14073
)
66
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
, vol. 
115
 (pg. 
896
-
908
)
67
Johnston
PV
Sasano
T
Mills
K
Evers
R
Lee
ST
Smith
RR
Lardo
AC
Lai
S
Steenbergen
C
Gerstenblith
G
Lange
R
Marban
E
Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy
Circulation
 , 
2009
, vol. 
120
 (pg. 
1075
-
1083
)
68
Andersen
DC
Andersen
P
Schneider
M
Jensen
HB
Sheikh
SP
Murine ‘cardiospheres’ are not a source of stem cells with cardiomyogenic potential
Stem Cells
 , 
2009
, vol. 
27
 (pg. 
1571
-
1581
)
69
Davis
DR
Ruckdeschel Smith
R
Marban
E
Human cardiospheres are a source of stem cells with cardiomyogenic potential
Stem Cells
 , 
2010
, vol. 
28
 (pg. 
903
-
904
)
70
Zaruba
MM
Soonpaa
M
Reuter
S
Field
LJ
Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts
Circulation
 , 
2010
, vol. 
121
 (pg. 
1992
-
2000
)
71
Murry
CE
Wiseman
RW
Schwartz
SM
Hauschka
SD
Skeletal myoblast transplantation for repair of myocardial necrosis
J Clin Invest
 , 
1996
, vol. 
98
 (pg. 
2512
-
2523
)
72
Taylor
DA
Atkins
BZ
Hungspreugs
P
Jones
TR
Reedy
MC
Hutcheson
KA
Glower
DD
Kraus
WE
Regenerating functional myocardium: improved performance after skeletal myoblast transplantation
Nat Med
 , 
1998
, vol. 
4
 (pg. 
929
-
933
)
73
Reinecke
H
Poppa
V
Murry
CE
Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting
J Mol Cell Cardiol
 , 
2002
, vol. 
34
 (pg. 
241
-
249
)
74
Reinecke
H
Minami
E
Poppa
V
Murry
CE
Evidence for fusion between cardiac and skeletal muscle cells
Circ Res
 , 
2004
, vol. 
94
 (pg. 
e56
-
e60
)
75
Reinecke
H
MacDonald
GH
Hauschka
SD
Murry
CE
Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair
J Cell Biol
 , 
2000
, vol. 
149
 (pg. 
731
-
740
)
76
Menasche
P
Hagege
AA
Vilquin
JT
Desnos
M
Abergel
E
Pouzet
B
Bel
A
Sarateanu
S
Scorsin
M
Schwartz
K
Bruneval
P
Benbunan
M
Marolleau
JP
Duboc
D
Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction
J Am Coll Cardiol
 , 
2003
, vol. 
41
 (pg. 
1078
-
1083
)
77
Herreros
J
Prosper
F
Perez
A
Gavira
JJ
Garcia-Velloso
MJ
Barba
J
Sanchez
PL
Canizo
C
Rabago
G
Marti-Climent
JM
Hernandez
M
Lopez-Holgado
N
Gonzalez-Santos
JM
Martin-Luengo
C
Alegria
E
Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction
Eur Heart J
 , 
2003
, vol. 
24
 (pg. 
2012
-
2020
)
78
Siminiak
T
Kalawski
R
Fiszer
D
Jerzykowska
O
Rzezniczak
J
Rozwadowska
N
Kurpisz
M
Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up
Am Heart J
 , 
2004
, vol. 
148
 (pg. 
531
-
537
)
79
Smits
PC
van Geuns
RJ
Poldermans
D
Bountioukos
M
Onderwater
EE
Lee
CH
Maat
AP
Serruys
PW
Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up
J Am Coll Cardiol
 , 
2003
, vol. 
42
 (pg. 
2063
-
2069
)
80
Menasche
P
Alfieri
O
Janssens
S
McKenna
W
Reichenspurner
H
Trinquart
L
Vilquin
JT
Marolleau
JP
Seymour
B
Larghero
J
Lake
S
Chatellier
G
Solomon
S
Desnos
M
Hagege
AA
The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation
Circulation
 , 
2008
, vol. 
117
 (pg. 
1189
-
1200
)
81
Dib
N
Michler
RE
Pagani
FD
Wright
S
Kereiakes
DJ
Lengerich
R
Binkley
P
Buchele
D
Anand
I
Swingen
C
Di Carli
MF
Thomas
JD
Jaber
WA
Opie
SR
Campbell
A
McCarthy
P
Yeager
M
Dilsizian
V
Griffith
BP
Korn
R
Kreuger
SK
Ghazoul
M
MacLellan
WR
Fonarow
G
Eisen
HJ
Dinsmore
J
Diethrich
E
Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up
Circulation
 , 
2005
, vol. 
112
 (pg. 
1748
-
1755
)
82
Chachques
JC
Herreros
J
Trainini
J
Juffe
A
Rendal
E
Prosper
F
Genovese
J
Autologous human serum for cell culture avoids the implantation of cardioverter-defibrillators in cellular cardiomyoplasty
Int J Cardiol
 , 
2004
, vol. 
95
 
Suppl. 1
(pg. 
S29
-
S33
)
83
Macia
E
Boyden
PA
Stem cell therapy is proarrhythmic
Circulation
 , 
2009
, vol. 
119
 (pg. 
1814
-
1823
)
84
Ly
HQ
Nattel
S
Stem cells are not proarrhythmic: letting the genie out of the bottle
Circulation
 , 
2009
, vol. 
119
 (pg. 
1824
-
1831
)
85
Siminiak
T
Fiszer
D
Jerzykowska
O
Grygielska
B
Rozwadowska
N
Kalmucki
P
Kurpisz
M
Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
1188
-
1195
)
86
Kang
HJ
Kim
HS
Zhang
SY
Park
KW
Cho
HJ
Koo
BK
Kim
YJ
Soo Lee
D
Sohn
DW
Han
KS
Oh
BH
Lee
MM
Park
YB
Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial
Lancet
 , 
2004
, vol. 
363
 (pg. 
751
-
756
)
87
Ince
H
Petzsch
M
Kleine
HD
Eckard
H
Rehders
T
Burska
D
Kische
S
Freund
M
Nienaber
CA
Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial infarction: final 1-year results of the Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI) Trial
Circulation
 , 
2005
, vol. 
112
 (pg. 
I73
-
I80
)
88
Valgimigli
M
Rigolin
GM
Cittanti
C
Malagutti
P
Curello
S
Percoco
G
Bugli
AM
Della Porta
M
Bragotti
LZ
Ansani
L
Mauro
E
Lanfranchi
A
Giganti
M
Feggi
L
Castoldi
G
Ferrari
R
Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
1838
-
1845
)
89
Hill
JM
Syed
MA
Arai
AE
Powell
TM
Paul
JD
Zalos
G
Read
EJ
Khuu
HM
Leitman
SF
Horne
M
Csako
G
Dunbar
CE
Waclawiw
MA
Cannon
RO
3rd
Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease
J Am Coll Cardiol
 , 
2005
, vol. 
46
 (pg. 
1643
-
1648
)
90
Zohlnhöfer
D
Dibra
A
Koppara
T
de Waha
A
Ripa
RS
Kastrup
J
Valgimigli
M
Schomig
A
Kastrati
A
Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
1429
-
1437
)
91
Achilli
F
Malafronte
C
Lenatti
L
Gentile
F
Dadone
V
Gibelli
G
Maggiolini
S
Squadroni
L
Di Leo
C
Burba
I
Pesce
M
Mircoli
L
Capogrossi
MC
Di Lelio
A
Camisasca
P
Morabito
A
Colombo
G
Pompilio
G
Granulocyte colony-stimulating factor attenuates left ventricular remodelling after acute anterior STEMI: results of the single-blind, randomized, placebo-controlled multicentre STem cEll Mobilization in Acute Myocardial Infarction (STEM-AMI) Trial
Eur J Heart Fail
 , 
2010
, vol. 
12
 (pg. 
1111
-
1121
)
92
Zaruba
MM
Theiss
HD
Vallaster
M
Mehl
U
Brunner
S
David
R
Fischer
R
Krieg
L
Hirsch
E
Huber
B
Nathan
P
Israel
L
Imhof
A
Herbach
N
Assmann
G
Wanke
R
Mueller-Hoecker
J
Steinbeck
G
Franz
WM
Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction
Cell Stem Cell
 , 
2009
, vol. 
4
 (pg. 
313
-
323
)
93
Jujo
K
Hamada
H
Iwakura
A
Thorne
T
Sekiguchi
H
Clarke
T
Ito
A
Misener
S
Tanaka
T
Klyachko
E
Kobayashi
K
Tongers
J
Roncalli
J
Tsurumi
Y
Hagiwara
N
Losordo
DW
CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction
Proc Natl Acad Sci USA
 , 
2010
, vol. 
107
 (pg. 
11008
-
11013
)
94
Kofidis
T
de Bruin
JL
Yamane
T
Tanaka
M
Lebl
DR
Swijnenburg
RJ
Weissman
IL
Robbins
RC
Stimulation of paracrine pathways with growth factors enhances embryonic stem cell engraftment and host-specific differentiation in the heart after ischemic myocardial injury
Circulation
 , 
2005
, vol. 
111
 (pg. 
2486
-
2493
)
95
Rajasingh
J
Bord
E
Hamada
H
Lambers
E
Qin
G
Losordo
DW
Kishore
R
STAT3-dependent mouse embryonic stem cell differentiation into cardiomyocytes: analysis of molecular signaling and therapeutic efficacy of cardiomyocyte precommitted mES transplantation in a mouse model of myocardial infarction
Circ Res
 , 
2007
, vol. 
101
 (pg. 
910
-
918
)
96
Cao
F
Lin
S
Xie
X
Ray
P
Patel
M
Zhang
X
Drukker
M
Dylla
SJ
Connolly
AJ
Chen
X
Weissman
IL
Gambhir
SS
Wu
JC
In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery
Circulation
 , 
2006
, vol. 
113
 (pg. 
1005
-
1014
)
97
Amariglio
N
Hirshberg
A
Scheithauer
BW
Cohen
Y
Loewenthal
R
Trakhtenbrot
L
Paz
N
Koren-Michowitz
M
Waldman
D
Leider-Trejo
L
Toren
A
Constantini
S
Rechavi
G
Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient
PLoS Med
 , 
2009
, vol. 
6
 pg. 
e1000029
 
98
Behfar
A
Perez-Terzic
C
Faustino
RS
Arrell
DK
Hodgson
DM
Yamada
S
Puceat
M
Niederländer
N
Alekseev
AE
Zingman
LV
Terzic
A
Cardiopoietic programming of embryonic stem cells for tumor-free heart repair
J Exp Med
 , 
2007
, vol. 
204
 (pg. 
405
-
420
)
99
Takahashi
K
Yamanaka
S
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Cell
 , 
2006
, vol. 
126
 (pg. 
663
-
676
)
100
Gurdon
JB
Melton
DA
Nuclear reprogramming in cells
Science
 , 
2008
, vol. 
322
 (pg. 
1811
-
1815
)
101
Mauritz
C
Schwanke
K
Reppel
M
Neef
S
Katsirntaki
K
Maier
LS
Nguemo
F
Menke
S
Haustein
M
Hescheler
J
Hasenfuss
G
Martin
U
Generation of functional murine cardiac myocytes from induced pluripotent stem cells
Circulation
 , 
2008
, vol. 
118
 (pg. 
507
-
517
)
102
Zhang
J
Wilson
GF
Soerens
AG
Koonce
CH
Yu
J
Palecek
SP
Thomson
JA
Kamp
TJ
Functional cardiomyocytes derived from human induced pluripotent stem cells
Circ Res
 , 
2009
, vol. 
104
 (pg. 
e30
-
e41
)
103
Moretti
A
Bellin
M
Welling
A
Jung
CB
Lam
JT
Bott-Flugel
L
Dorn
T
Goedel
A
Hohnke
C
Hofmann
F
Seyfarth
M
Sinnecker
D
Schomig
A
Laugwitz
KL
Patient-specific induced pluripotent stem-cell models for long-QT syndrome
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
1397
-
1409
)
104
Rosenzweig
A
Illuminating the potential of pluripotent stem cells
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
1471
-
1472
)
105
Nelson
TJ
Martinez-Fernandez
A
Yamada
S
Perez-Terzic
C
Ikeda
Y
Terzic
A
Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells
Circulation
 , 
2009
, vol. 
120
 (pg. 
408
-
416
)
106
Swijnenburg
RJ
Schrepfer
S
Govaert
JA
Cao
F
Ransohoff
K
Sheikh
AY
Haddad
M
Connolly
AJ
Davis
MM
Robbins
RC
Wu
JC
Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts
Proc Natl Acad Sci USA
 , 
2008
, vol. 
105
 (pg. 
12991
-
12996
)
107
Nelson
TJ
Martinez-Fernandez
A
Terzic
A
Induced pluripotent stem cells: developmental biology to regenerative medicine
Nat Rev Cardiol
 , 
2010
, vol. 
7
 (pg. 
700
-
710
)
108
Sorrentino
SA
Bahlmann
FH
Besler
C
Muller
M
Schulz
S
Kirchhoff
N
Doerries
C
Horvath
T
Limbourg
A
Limbourg
F
Fliser
D
Haller
H
Drexler
H
Landmesser
U
Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone
Circulation
 , 
2007
, vol. 
116
 (pg. 
163
-
173
)
109
Murasawa
S
Llevadot
J
Silver
M
Isner
JM
Losordo
DW
Asahara
T
Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells
Circulation
 , 
2002
, vol. 
106
 (pg. 
1133
-
1139
)
110
Yamaguchi
J
Kusano
KF
Masuo
O
Kawamoto
A
Silver
M
Murasawa
S
Bosch-Marce
M
Masuda
H
Losordo
DW
Isner
JM
Asahara
T
Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization
Circulation
 , 
2003
, vol. 
107
 (pg. 
1322
-
1328
)
111
Assmus
B
Urbich
C
Aicher
A
Hofmann
WK
Haendeler
J
Rossig
L
Spyridopoulos
I
Zeiher
AM
Dimmeler
S
HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes
Circ Res
 , 
2003
, vol. 
92
 (pg. 
1049
-
1055
)
112
Vasa
M
Fichtlscherer
S
Adler
K
Aicher
A
Martin
H
Zeiher
AM
Dimmeler
S
Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease
Circulation
 , 
2001
, vol. 
103
 (pg. 
2885
-
2890
)
113
Dimmeler
S
Aicher
A
Vasa
M
Mildner-Rihm
C
Adler
K
Tiemann
M
Rutten
H
Fichtlscherer
S
Martin
H
Zeiher
AM
HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway
J Clin Invest
 , 
2001
, vol. 
108
 (pg. 
391
-
397
)
114
Bahlmann
FH
de Groot
K
Mueller
O
Hertel
B
Haller
H
Fliser
D
Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists
Hypertension
 , 
2005
, vol. 
45
 (pg. 
526
-
529
)
115
Penn
MS
Mangi
AA
Genetic enhancement of stem cell engraftment, survival, and efficacy
Circ Res
 , 
2008
, vol. 
102
 (pg. 
1471
-
1482
)
116
Chavakis
E
Koyanagi
M
Dimmeler
S
Enhancing the outcome of cell therapy for cardiac repair: progress from bench to bedside and back
Circulation
 , 
2010
, vol. 
121
 (pg. 
325
-
335
)
117
Giannotti
G
Doerries
C
Mocharla
PS
Mueller
MF
Bahlmann
FH
Horvath
T
Jiang
H
Sorrentino
SA
Steenken
N
Manes
C
Marzilli
M
Rudolph
KL
Luscher
TF
Drexler
H
Landmesser
U
Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction
Hypertension
 , 
2010
, vol. 
55
 (pg. 
1389
-
1397
)
118
Taljaard
M
Ward
MR
Kutryk
MJ
Courtman
DW
Camack
NJ
Goodman
SG
Parker
TG
Dick
AJ
Galipeau
J
Stewart
DJ
Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): the first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction
Am Heart J
 , 
2010
, vol. 
159
 (pg. 
354
-
360
)
119
Mias
C
Trouche
E
Seguelas
MH
Calcagno
F
Dignat-George
F
Sabatier
F
Piercecchi-Marti
MD
Daniel
L
Bianchi
P
Calise
D
Bourin
P
Parini
A
Cussac
D
Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney
Stem Cells
 , 
2008
, vol. 
26
 (pg. 
1749
-
1757
)
120
Bartunek
J
Croissant
JD
Wijns
W
Gofflot
S
de Lavareille
A
Vanderheyden
M
Kaluzhny
Y
Mazouz
N
Willemsen
P
Penicka
M
Mathieu
M
Homsy
C
De Bruyne
B
McEntee
K
Lee
IW
Heyndrickx
GR
Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium
Am J Physiol Heart Circ Physiol
 , 
2007
, vol. 
292
 (pg. 
H1095
-
H1104
)
121
Hahn
JY
Cho
HJ
Kang
HJ
Kim
TS
Kim
MH
Chung
JH
Bae
JW
Oh
BH
Park
YB
Kim
HS
Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
933
-
943
)
122
Laflamme
MA
Murry
CE
Regenerating the heart
Nat Biotechnol
 , 
2005
, vol. 
23
 (pg. 
845
-
856
)
123
Mooney
DJ
Vandenburgh
H
Cell delivery mechanisms for tissue repair
Cell Stem Cell
 , 
2008
, vol. 
2
 (pg. 
205
-
213
)
124
Tongers
J
Webber
MJ
Losordo
DW
Bioengineering to enhance progenitor cell therapeutics
Tex Heart Inst J
 , 
2009
, vol. 
36
 (pg. 
140
-
144
)
125
Davis
ME
Motion
JP
Narmoneva
DA
Takahashi
T
Hakuno
D
Kamm
RD
Zhang
S
Lee
RT
Injectable self-assembling peptide nanofibers create intramyocardial microenvironments for endothelial cells
Circulation
 , 
2005
, vol. 
111
 (pg. 
442
-
450
)
126
Davis
ME
Hsieh
PC
Grodzinsky
AJ
Lee
RT
Custom design of the cardiac microenvironment with biomaterials
Circ Res
 , 
2005
, vol. 
97
 (pg. 
8
-
15
)
127
Padin-Iruegas
ME
Misao
Y
Davis
ME
Segers
VF
Esposito
G
Tokunou
T
Urbanek
K
Hosoda
T
Rota
M
Anversa
P
Leri
A
Lee
RT
Kajstura
J
Cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers improve endogenous and exogenous myocardial regeneration after infarction
Circulation
 , 
2009
, vol. 
120
 (pg. 
876
-
887
)
128
Davis
ME
Hsieh
PC
Takahashi
T
Song
Q
Zhang
S
Kamm
RD
Grodzinsky
AJ
Anversa
P
Lee
RT
Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction
Proc Natl Acad Sci USA
 , 
2006
, vol. 
103
 (pg. 
8155
-
8160
)
129
Tongers
J
Webber
MG
Renault
M-A
Roncalli
JG
Jujo
K
Wu
X
Klyachko
E
Thorne
T
Stupp
SI
Losordo
DW
Abstract 4931: RGDS-epitope presenting peptide amphiphile nanofibers enhance therapeutic potency of cell-based strategies in ischemic tissue
Circulation
 , 
2009
, vol. 
120
 pg. 
S1023-c-1024
 
130
Segers
VF
Tokunou
T
Higgins
LJ
MacGillivray
C
Gannon
J
Lee
RT
Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction
Circulation
 , 
2007
, vol. 
116
 (pg. 
1683
-
1692
)
131
Zimmermann
WH
Melnychenko
I
Wasmeier
G
Didié
M
Naito
H
Nixdorff
U
Hess
A
Budinsky
L
Brune
K
Michaelis
B
Dhein
S
Schwoerer
A
Ehmke
H
Eschenhagen
T
Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts
Nat Med
 , 
2006
, vol. 
12
 (pg. 
452
-
458
)
132
Avgoustiniatos
ES
Colton
CK
Effect of external oxygen mass transfer resistances on viability of immunoisolated tissue
Ann N Y Acad Sci
 , 
1997
, vol. 
831
 (pg. 
145
-
167
)
133
Melero-Martin
JM
De Obaldia
ME
Kang
SY
Khan
ZA
Yuan
L
Oettgen
P
Bischoff
J
Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells
Circ Res
 , 
2008
, vol. 
103
 (pg. 
194
-
202
)
134
Terrovitis
J
Lautamaki
R
Bonios
M
Fox
J
Engles
JM
Yu
J
Leppo
MK
Pomper
MG
Wahl
RL
Seidel
J
Tsui
BM
Bengel
FM
Abraham
MR
Marban
E
Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1619
-
1626
)
135
Aicher
A
Heeschen
C
Sasaki
K
Urbich
C
Zeiher
AM
Dimmeler
S
Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia
Circulation
 , 
2006
, vol. 
114
 (pg. 
2823
-
2830
)
136
Zen
K
Okigaki
M
Hosokawa
Y
Adachi
Y
Nozawa
Y
Takamiya
M
Tatsumi
T
Urao
N
Tateishi
K
Takahashi
T
Matsubara
H
Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic response
J Mol Cell Cardiol
 , 
2006
, vol. 
40
 (pg. 
799
-
809
)
137
Ghanem
A
Steingen
C
Brenig
F
Funcke
F
Bai
ZY
Hall
C
Chin
CT
Nickenig
G
Bloch
W
Tiemann
K
Focused ultrasound-induced stimulation of microbubbles augments site-targeted engraftment of mesenchymal stem cells after acute myocardial infarction
J Mol Cell Cardiol
 , 
2009
, vol. 
47
 (pg. 
411
-
418
)
138
Bartunek
J
Dimmeler
S
Drexler
H
Fernandez-Aviles
F
Galinanes
M
Janssens
S
Martin
J
Mathur
A
Menasche
P
Priori
S
Strauer
B
Tendera
M
Wijns
W
Zeiher
A
The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for repair of the heart
Eur Heart J
 , 
2006
, vol. 
27
 (pg. 
1338
-
1340
)

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