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Cardiovascular Research 2003 58(2):351-357; doi:10.1016/S0008-6363(02)00769-1
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Copyright © 2003, European Society of Cardiology

Skeletal muscle satellite cell transplantation

Philippe Menasché*

Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France

* Tel.: +33-1-4025-6721; fax: +33-1-4025-6754. philippe.menasche{at}hop.egp.ap-hop-paris.fr

Received 23 August 2002; accepted 28 October 2002


   Abstract
Top
 Abstract
1 Rationale
 2 Experimental background
 3 Routes of cell...
 4 Clinical observations
 References
 
Cell transplantation is currently gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is primarily caused by the loss of a critical number of cardiomyocytes and that their replacement by new contractile cells could functionally ‘regenerate’ postinfarction scars in which these cells are implanted. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also considered, particularly bone marrow stem cells which are attractive because of their autologous origin and their purported cardiomyocyte/endothelial transdifferentiation potential in response to cues present in the target organ. However, several key issues still need to be addressed including (1) the optimal type of donor cells, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, and (4) the potential benefits of cell transplantation in nonischemic dilated cardiomyopathies. In parallel to the experimental studies designed to address these issues, clinical trials are underway and their results should hopefully allow the assessment of to what extent cellular therapy may improve the outcome of patients with heart failure.

KEYWORDS Heart failure; Stem cells; Transplantation

The management of patients with heart failure is receiving a growing and continued interest because of the increase in both the prevalence (approximately 5 million US citizens) and incidence (400 000–600 000 new patients every year) of this condition. The magnitude of the problem is even expected to be still greater in the forthcoming years because of the increasing age of the population and the improved postinfarction survival rates resulting from new drug- and device-based therapeutic developments.

Contemporary medical therapy has dramatically improved the prognosis of heart failure and new drugs currently under investigation might further improve patient outcomes. In many cases, however, medical therapy is simply palliative and only shifts the survival curve rightwards, which accounts for a persistently high mortality which can reach 60% within 1 year for patients in New York Heart Association functional class IV. These figures obviously translate into tremendous financial costs which are primarily hospital-driven so that heart failure is currently estimated to consume 1–2% of the total health care budget of western countries [1].

Although cardiac transplantation remains the only radical treatment of the most advanced forms of heart failure, the limitations of this approach, largely related to organ shortage, have led to a continuous strive for designing alternate options. Most of them have focused on reshaping the dilated left ventricle, primarily by endocardial patch plasty, but also more recently by passive constraint (Acorn®) and shape-change (Myosplint®, Cardioclasp®), devices. In parallel, substantial improvements have been made in left ventricular assist devices, particularly as destination therapy [2] but the use of permanently implantable blood pumps still remains investigational. In patients with wide QRS complexes, cardiac resynchronization has also emerged as a promising treatment [3], which does not exclude additional approaches more directly targeted at improving pump function. In this setting, cell transplantation is currently generating a great deal of interest which, schematically, is proportional to the increased skepticism of several investigators about the relevance of gene therapy to the clinical management of patients with heart failure.


   1 Rationale
Top
 Abstract
 1 Rationale
2 Experimental background
 3 Routes of cell...
 4 Clinical observations
 References
 
The overall objective of cell therapy is to repopulate postinfarction scar tissue with contractile cells that can engraft in sufficient numbers to replace dead cardiac myocytes and restore functionality in these akinetic areas. Conceptually, this objective can be achieved through three distinct approaches. The first consists of stimulating residual cardiomyocytes to reenter a mitotic cycle. However, although cardiomyocytes of infarcted or failing human hearts have been shown to undergo mitoses [4,5], this regenerative capacity is by far too limited to compensate for the loss of cardiac cells resulting from a large infarct. The second strategy is based on gene therapy and is targeted at the transformation of in-scar fibroblasts into contractile cells by transfection with the MyoD master gene which controls the skeletal muscle differentiation programme. Although this approach has yielded some successful experimental results [6], it is fraught with the multiple issues still associated with gene therapy and is still of limited clinical relevance.

The third approach is based on the provision of exogenously supplied contractile cells as surrogate cardiomyocytes into the scar. From a clinical standpoint, this ‘transplantation’ strategy is likely the most realistic and, consequently, has been extensively investigated in the laboratory setting before being tested in the first human trial. Of note, most of these experiments have focused on ischemic, segmental cardiomyopathies; however, preliminary results of ongoing studies yet suggest that the putative benefits of cellular transplantation might be equally relevant to globally dilated cardiomyopathies, whether idiopathic [7] or caused by doxorubicin toxicity [8].


   2 Experimental background
Top
 Abstract
 1 Rationale
 2 Experimental background
3 Routes of cell...
 4 Clinical observations
 References
 
The prerequisite for implanted cells to improve cardiac function is that they feature contractile properties. Both fetal (and neonatal) cardiomyocytes and skeletal myoblasts fall into this category.

Studies with fetal and neonatal cardiomyocytes have been historically pivotal to establish the ‘proof-of-concept’ by showing, in rodent models of coronary artery ligation or cryoinjury-induced myocardial infarction, that these cells formed stable intracardiac grafts, were coupled with host cardiomyocytes through connexin-43-supported gap junctions and improved left ventricular function [9–11]. Recent data have further shown that grafted neonatal cardiomyocytes were still detectable in infarcted areas up to 6 months after transplantation and were associated with thickening of the left ventricular wall, increased ejection fraction and reduced dyskinesis, as assessed by biplane angiography [12]. That transplanted cells can physiologically integrate within the host tissue is further supported by the findings that fetal cells harvested from the sino-atrial area can exert a pacemaker activity following their transplantation in recipient animals whose conduction system has been irreversibly damaged [13]. However, in a clinical perspective, the transplantation of fetal or neonatal cardiac cells raises significant issues related to ethics, availability and immunogenicity which question the widescale clinical applicability of this approach and account for the great deal of interest paid to the alternate variant of intrinsically contractile cells, i.e. skeletal myoblasts.

These myogenic precursors (known as satellite cells) normally lie in a quiescent state under the basal membrane of skeletal muscular fibers. Following tissue injury, they are rapidly mobilized, proliferate and fuse, thereby effecting repair and regeneration of the damaged fibers. In a clinical perspective, these cells feature several attractive characteristics: (i) an autologous origin which overcomes all problems related to availability, ethics and immunogenicity and is a key factor for large-scale clinical applicability, (ii) a high proliferative potential under appropriate culture conditions, (iii) a commitment to a well-differentiated myogenic lineage which virtually eliminates the risk of tumoreginicity, and (iv) a high resistance to ischemia, which is a major advantage given the avascular nature of postinfarct scars in which they are to be implanted.

Analysis of the bulk of experimental data on myoblast transplantation leads to the main following conclusions. Morphologically, the injected myoblasts differentiate into typical multinucleated myotubes which, in a sheep model of myocardial infarction, tend to repopulate the areas of fibrosis [14]. Although we and others [15] have failed to show any morphological change of the injected cells into cardiomyocytes, engrafted myotubes coexpress fast, skeletal muscle-type and slow myosin [15]. Indeed, the proportion of fibers demonstrating a purely slow or composite (fast and slow) myosin isoform pattern increases over time. This observation suggests that factors associated with the myocardial environment (stretch and/or repeated electromechanical stimulation) may lead to some phenotypic adaptation similar to that previously reported after dynamic cardiomyoplasty. In contrast, however, to fetal cardiomyocytes, engrafted skeletal myotubes do not seem to physically couple with host cardiac cells. Indeed, cultured skeletal myoblasts express N-cadherin and connexin-43 (the major proteins constituents of fascia adherens and gap junctions and therefore responsible for mechanical and electrical coupling, respectively, in heart tissue) but expression of these proteins is downregulated following intramyocardial implantation [16].

The functional correlate of these observations is an improvement in left ventricular function which has now been demonstrated in small and large animal models of myocardial infarction created by coronary artery ligation, cryoinjury or toxic chemicals [14,17–20]. A causal relationship between the engraftment of cells and the functional outcome is strongly suggested by the data of Taylor et al. [18] who could only document an improved function in cryoinjured rabbit hearts where autologous myoblasts were successfully identified. Importantly, the functional benefits of myoblast grafting seem to be sustained over time, as suggested by our 1-year follow-up data which show ejection fraction values unchanged from those measured at the 4-month post-transplant study point [21]. This long-term benefit could conceivably be related to the expression of slow myosin by engrafted fibers and their subsequent ability to withstand fatigue when subjected to a cardiac-type workload [15]. Finally, although we have found that the post-transplant improvement in function (compared with hearts injected with culture medium alone) was tightly related to the number of injected myoblasts [22], another study (which did not include a functional assessment) has failed to document an increase in graft size with increasing donor cardiomyocyte cell number [23]. Dose-escalation studies are clearly required to better characterize the relationship between the number of grafted myoblasts and the functional outcome.

The mechanism(s) by which implanted myoblasts improve function have not yet been elucidated and at least three hypotheses, which are not mutually exclusive, can be put forward.

First, the elastic properties of implanted cells could act as a scaffold strengthening the ventricular wall and subsequently limiting postinfarct scar expansion. It is also conceivable that implanted cells secrete factors leading to a reorganization of the extracellular matrix. Thus, it would be particularly important to determine whether myoblast engraftment is associated with inhibition of matrix metalloproteinases and/or increase in myocardial fibrillar collagen network [24] as an improved structural support for both grafted cells and residual native cardiomyocytes might contribute to limit excessive remodeling. However, although such a mechanism may be operative when cells are injected at a relatively early stage after the infarction, and would thus prevent ventricular dilatation, it is less likely that myoblast grafts can reverse an already completed remodeling process, as suggested by our clinical observation of unchanged end-diastolic volumes in patients having undergone late myoblast implantation in old infarcts.

In this context, the second hypothesis which postulates a direct contribution of grafted cells to improved systolic function is particularly attractive. This hypothesis is admittedly challenged by the observation that engrafted myoblasts are not physically connected to host cardiomyocytes through connexin-43-supported gap junctions since, as previously mentioned, this protein is downregulated after transplantation. There is, however, a bunch of indirect arguments suggesting that the lack of positive staining for connexin 43 does not automatically preclude a role for implanted myoblasts in the post-transplant enhancement of contractility: (i) a conditional knockout for connexin-43 strain of mice has been developed [25] and although these animals prematurely die from arrhythmias, they demonstrate normal heart function until their death; in line with this observation, our earlier comparison [26] between fetal cardiomyocytes (which express connexin 43) and skeletal myoblasts (which do not) had failed to show any difference in the magnitude of functional improvement following transplantation; (ii) only cells which feature intrinsically contractile properties improve systolic function whereas cells lacking this property like fibroblasts only effect diastolic function by limiting infarct expansion [27]; (iii) both pressure–volume loops [21] and tissue doppler imaging [14] have provided more direct evidence that engrafted skeletal myoblasts increase global and regional contractile function, respectively; (iv) on electron microscopy, intramyocardially generated skeletal myotubes display well defined striations which suggest that the contractile apparatus of these cells may be operative; (v) in our phase I clinical trial, 60% of the segments of scarred tissue which have been implanted with myoblasts display a new-onset contractility manifest as systolic thickening of the grafted wall which is consistent with an active contraction of cells rather than with a passive motion due to tethering of the grafted area to the neighbouring viable myocardium. Admittedly, all these surrogate arguments only provide indirect evidence for the involvement of grafted myoblasts in active contraction. Consequently, a model is being developed in our laboratory to directly monitor the behavior of in situ engrafted myoblasts and try to sort out the patterns of coupling between these cells and host cardiomyocytes. As a synchronous propagation of electrical impulses through specialized intercellular junctions is unlikely, alternate mechanisms have to be considered, such as a stretch-induced contraction of transplanted cells in response to the contraction of surrounding recipient cardiomyocytes [28]. This mechanism implies, however, some physical link between grafted myoblasts and the extracellular matrix to which native cardiomyocytes are otherwise connected. This link could be provided by binding of myoblasts to integrins, the role of which is not restricted to mediation of cell adhesion but also encompasses signal transduction. Another possible mechanism involves a field effect [29] whereby electrical currents generated by the pool of normally contractile cardiomyocytes would be directly channelled through membranes to evoke action potentials from the excitable in-scar skeletal muscle cells. Ultimately, transfection of myoblasts with the gene encoding connexin 43 [30] could be an interesting approach for reestablishing cell-to-cell communications closer to the physiological situation and thus potentially improve the functional benefits of the transplantation procedure.

The third hypothesis is that transplanted cells behave as platforms releasing growth and/or angiogenic factors. Such a mechanism is currently not supported by our experimental findings that myoblast transplantation fails to increase angiogenesis beyond that seen in control hearts receiving an equivalent volume of cell-free culture medium alone. However, paracrine effects exerted by grafted myoblasts on putative resident cardiac precursor cells [31] and triggering their differentiation into functionally effective cardiomyocytes cannot be completely excluded. In line with this assumption, myoblast-induced changes in the extracellular matrix resulting in a better preservation of the collagen–integrin–myocyte cytoskeletal complex could translate into an improved transduction of myocyte shortening into overall left ventricular ejection.

Although the previously mentioned characteristics of skeletal myoblasts have made them attractive candidates for ‘first generation’ cell transplantation, alternate cell types are being considered for clinical use. Among them, embryonic stem cells are still associated with major ethical, regulatory, technical and safety hurdles that make human applications unlikely in the near future. Such is not the case for bone marrow stem cells which have already entered the clinical arena in spite of experimental data which are far less robust than those available when the skeletal myoblast phase I trial was initiated. Thus, there are anecdotal observations of in-scar extemporaneous transplantation of fresh, unfractionated bone marrow aspirated at the time of the percutaneous or surgical procedure and immediately reinjected. While the simplicity of this approach makes it clinically appealing, our yet unpublished experimental data suggest that it is completely ineffective in inducing a cardiomyogenic and/or endothelial differentiation and, correlatively, in improving postinfarct function. The use of hematopoietic progenitors is likely more promising [32–34] because some form of transdifferentiation can logically be expected from these relatively immature, and consequential ‘pluripotential’ cells. More work, however, needs to be done to validate this hypothesis, select the optimal subpopulation, address the scale-up issue (these progenitors are present in minute amounts in unstimulated bone marrow and blood, which probably accounts for the failure of total fresh bone marrow transplantation to have any benefit) and confirm that expanded progenitors may have a true regenerating effect on postinfarction scars (and not only an angiogenic effect on ischemic myocardium). A last possibility would be the use of bone marrow stromal cells but their preimplantation culture in the presence of 5-azacytidine seems to be a prerequisite for driving them towards a purportedly cardiomyogenic lineage [35]. This might seriously hamper the clinical applicability of the stromal cell-based approach because of the safety issues raised by the exposure of cells to this compound.


   3 Routes of cell delivery
Top
 Abstract
 1 Rationale
 2 Experimental background
 3 Routes of cell...
4 Clinical observations
 References
 
So far, cell injections have usually been accomplished under direct control, through multiple epicardial punctures. To reduce the invasiveness of the procedure, percutaneous approaches are currently undergoing a largely industry-driven extensive development. In spite of the successful results reported with the intracoronary arterial route [36], more emphasis is put on endoventricular injections which benefit from improvements in catheter design and navigation systems. Surprisingly, however, the growing number of patients undergoing these procedures (which provide wonderful opportunities for life case shows) sharply contrasts with the lack of robust animal data showing (as it has been the case for epicardial injections) that this ‘blind’ approach is not only technically feasible but also functionally efficacious. A recent experimental study [37] has reported a higher intramyocardial retention of microspheres after endoventricular injections compared with epicardial injections but these results may not be readily applicable to the use of cells.

Regardless of the route, a major issue associated with cell transplantation remains the extremely high rate of early cell death. In a rat model of cryoinjury, Zhang et al. [23] have estimated that approximately 90% of the transplanted cardiomyocytes died over the first week, with half of the deaths occurring over the first 24 h. Using a coronary artery ligation model, we have come to quantitatively similar conclusions regarding the death rate of transplanted skeletal myoblasts. Still lower survival rates (0.44% after 4 days) have been reported following injections of human mesenchymal stem cells into normal mouse myocardium [38]. However, by comparing a genomic (Y chromosome) and semiconserved (a radiolabel) marker, Beauchamp et al. [39] have shown that at the time where only 1% of the radiolabel persisted following transplantation of myoblasts into muscles of dystrophic mice, the mean percentage of Y chromosome present was equivalent to 23.5% of the initial population, thereby suggesting maintenance of the proliferation potential of a distinct, behaviorally more resistant subpopulation. Although the morphological demonstration of engrafted myotubes and the related improvement in function reported in models of myocardial infarction suggest that similar survival patterns may occur in heart tissue, it is sound to postulate that the benefits of the procedure should be further enhanced by limitation of cell death.

This, in turn, requires a basic understanding of the mechanism(s) of this high attrition. Several factors are likely to be involved, including physical strain during injections (which should be handled by improved delivery devices), inflammation, ischemia and apoptosis. The observation [23] that the percentage of apoptotic cells (as assessed by TUNEL staining) was reduced by 50% when cardiomyocytes were injected at a delayed stage, into a well vascularized granulation tissue, as opposed to an early delivery in an acutely cryoinjured myocardium, emphasizes the role of the ischemic/hypoxic environment in the genesis of cell death and suggest the possible benefits of providing a vascular support to the grafted cells. This view is actually consistent with the previously reported benefits yielded by transfected myoblasts (derived from an immortalized line) overexpressing vascular endothelial growth factor [40]. An alternate approach for enhancing cell survival could be to subject them to a heat shock during the late stages of the culture process. Whatever the mechanisms involved, heat shock pretreatment has been shown to reduce by one half the rate of cardiomyocyte death [23] and to exert similarly protective effects on the previously mentioned immortalized line of skeletal myoblasts [41]. It is likely that, in the future, combined adjunctive treatments should allow the reduction of the rate of early post-transplantation cell death and, consequently, optimize the functional efficacy of the procedure.


   4 Clinical observations
Top
 Abstract
 1 Rationale
 2 Experimental background
 3 Routes of cell...
 4 Clinical observations
References
 
We initiated the first phase I human trial of autologous skeletal myoblast transplantation on June 15, 2000 [42]. Eligibility for inclusion in this trial was based on the following three criteria: (i) impairment of left ventricular function (ejection fraction ≤0.35), (ii) history of myocardial infarct with a residual discrete, akinetic and nonviable scar, as assessed by dobutamine echocardiography and positron emission scan, and (iii) indication for concomitant coronary artery bypass grafting in remote, (i.e. different from the transplanted area), viable but ischemic myocardium.

The protocol involves three steps. First, a muscular biopsy is retrieved from the thigh under local anesthesia. This chunk of muscle is then minced and grown for 2–3 weeks in the Cell Cultures Laboratory so as to obtain a highly purified, viable and abundant cell yield (at least 400x106 cells and 50% myoblasts). Cells are subsequently reimplanted across the postinfarct scar while coronary bypass grafts are placed on diseased arteries supplying remote ischemic areas.

This phase I is now completed and the complete results will be published separately. It has allowed us to establish the feasibility of the procedure, as demonstrated by the ability to reach the target numbers of cells within the preset time frame (2–3 weeks). The operation, by itself, has turned out to be safe, without specific procedure-related complications. The only adverse event which might be ascribed to cell transplantation is sustained ventricular tachycardia, which has occurred in four patients during the early (3 weeks) postoperative period and, except for one case, were clinically well tolerated. The mechanisms of these arrhythmias are currently being investigated and might include, among others, inhomogeneity in action potential conduction creating reentry pathways, release of arrhythmogenic byproducts by the inflammatory cells invading the transplanted areas or disorganization of the extracellular matrix by the injectate. Regardless of the mechanism(s), our data suggest that the incidence and/or severity of these arrhythmias could be reduced by an appropriate prophylaxis by amiodarone. At most, implantation of a defibrillator may be required, which is not illogical in this high-risk subset of heart failure patients, in view of the survival benefits expected from the device, as reported in the MADIT II trial [43]. While the small sample size (ten patients) of our trial, the lack of a control group and the confounding effect of the concomitant revascularization preclude any definite conclusion, the finding that approximately 60% of the cell-implanted scar areas demonstrate a systolic thickening which was not present preoperatively is encouraging but needs to be validated by the results of the forthcoming phase II efficacy trial.

Other clinical trials are either underway or in the process of being implemented (a ten-patient safety study was reported by the group of T. Siminiak in Poland during one of the late-breaking trials sessions of the 2002 meeting of the European Society of Cardiology). It is hoped that their design will adhere to rigorous methodologic guidelines as this is the price to pay for accurately assessing whether, and to what extent, skeletal myoblast transplantation can really impact on the outcome of patients with advanced postinfarction left ventricular dysfunction. It is also important to keep in perspective the tight interplay between cell therapy and the two other new biologically-oriented approaches to heart failure, i.e. angiogenesis and gene therapy. Actually, angiogenesis is not primarily targeted at improving function of the failing myocardium, but rather at relieving ischemic symptoms in patients who are unsuitable candidates for more conventional forms of revascularization (angioplasty or bypass surgery). In animal models of myocardial ischemia, the ‘proof of concept’ has been brought by compelling data showing that administration of angiogenic growth factors like vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF), either as recombinant proteins or by gene transfer, could increase myocardial blood supply through neovascularization. The initial clinical trials using these factors (reviewed in [44]) have yielded rather encouraging although still mixed results and the current trend is to consider that efficacy of this approach most likely requires combined administration of different growth factors or delivery of a master gene (for example, hypoxia-inducible growth factor 1-{alpha}) that controls several downstream effectors. The issue of gene therapy is particularly complex in the case of heart failure which results from the dysregulation of several signaling pathways which complicates the identification of the candidate genes. In this setting, however, manipulation of three major areas have been investigated [45]: calcium handling, β-adrenergic signaling and apoptosis. Of special interest are the studies by Del Monte et al. [46] who have shown that overexpression of SERCA2a by adenoviral gene transfer in cardiomyocytes retrieved from failing human hearts increased both protein expression and pump activity, which correlated with the normalization of the major abnormalities of calcium handling. Although there is still a wide gap between laboratory findings and clinical applications as several efficacy (validation of results in large animals) and safety issues remain to be addressed, it is likely that cell transplantation may take advantage of advances in gene and vascular biology. Genetic manipulation of grafted cells to make them express cardioprotective recombinant proteins is just one example of such an interplay. Thus, cellular transplantation, angiogenesis and gene therapy should not be viewed as competitive but rather as complementary with the common and final goal of improving the outcome of heart failure patients.

Time for primary review 32 days.


   References
Top
 Abstract
 1 Rationale
 2 Experimental background
 3 Routes of cell...
 4 Clinical observations
 References
 

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