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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Skeletal myoblasts for cardiac repair in animal models

Juan J. Gavira¹, Gloria Abizanda², Maitane Pérez-Ilzarbe², Diego Martínez-Caro¹, Emilio Nasarre¹, Ana Pérez-Ruiz² and Felipe Prósper^2,*

¹ Department of Cardiology and Cardiovascular Surgery, Clinica Universitaria, University of Navarra, Navarra 31008, Spain
² Department of Hematology and Area of Cell Therapy, Clinica Universitaria, University of Navarra, Av Pio XII, 36. Pamplona, Navarra 31008, Spain

^* Corresponding author. E-mail address: fprosper{at}unav.es

	Abstract

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
Cell therapy for cardiovascular disease has become a major area of research. Among different types of stem cells used for cardiac repair, skeletal myoblasts (SkM) are not endowed with the potential to differentiate into functional cardiomyocytes. However, certain characteristics such as their potential to give rise to mature myofibres, to induce vasculogenesis, or to alter collagen deposition and decrease fibrosis after infarction as well as their resistance to hypoxia provide an argument for their use in cell therapy approaches of cardiac diseases. A vast experience accumulated during the last 15 years in different animal models of cardiac disease clearly indicates that transplantation of SkM in models of chronic myocardial infarction is associated with improvement of cardiac function. Understanding the mechanism by which SkM contributes to heart function and increasing cell engraftment while reducing invasiveness of the procedure are reasonable steps in order to improve the functional results of cell therapy with SkM. Here we discuss some of the current approaches aimed to improve cardiac cell therapy with SkM.

Key Words: Cardiovascular regeneration • Ischaemia • Skeletal myoblast • Chronic myocardial infarction • Fibrosis • Angiogenesis

	Introduction

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
The capacity of skeletal muscle to respond to injury by proliferation and differentiation of stem cells residing in the muscle has been known for a long time.¹ This regenerative capacity is provided by a small population of mononuclear cells named satellite cells and their progeny of skeletal myoblasts (SkM), which in response to injury proliferate and eventually fused to form multinucleated myotubes that eventually re-established the normal architecture of the muscle.² Unlike the skeletal muscle, the cardiac muscle lacks a significant capacity for regeneration, even though the existence of cardiac progenitor cells has recently been reported indicating a certain regeneration capacity,^3,4 and cardiomyocyte loss because of disease or injury is irreversible and typically results in the replacement of working cardiac tissue with non-functional scar tissue. Practical reasons such as the high proliferative potential under appropriate culture conditions allowing a substantial scale-up and a high resistance to ischaemia which would be expected to facilitate survival of cells in a hostile environment such as the scar tissue after myocardial infarction (MI) led to the hypothesis that transplantation of SkM in models of chronic MIs may results in a significant improvement in heart function and cardiac regeneration.

	Cardiac repair with skeletal myoblasts in animal models

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
Since the initial report from Marelli et al.⁵ in which SkM were transplanted in a dog model of MI, more than 100 studies in small and large animal models of MI have demonstrated the feasibility of this approach (review in ref. 6). These studies have consistently shown that transplanted cells engraft and differentiate into multinucleated myotubes⁷ acquiring some characteristics of cardiac muscle expression of slow-twitch myosin heavy chain (MHC),⁸ but do not differentiate into functional cardiomyocytes⁹ or establish electromechanical coupling with the host cardiomyocytes.¹⁰ Although most studies using SkM have been developed in models of chronic MI, it has recently been suggested that SkM can also be useful in models of non-ischaemic cardiomyopathy. Direct injection of SkM in a Hamster model of dilated cardiomyopathy was associated with significant engraftment, differentiation of SkM into myofibres, and improved cardiac performance.¹¹ Similarly, in a rat model of dilated cardiomyopathy induced by injection of Trypanosoma cruzei, the causal agent of Chagas disease, transplantation of SkM previously co-cultured with mesenchymal stem cells significantly improved ejection fraction and reduced left ventricular end diastolic volumen and left ventricular end systlic volumen 4 weeks after transplant.¹² Instead of using a direct delivery of the cells into the myocardium, Yacoub and coworkers¹³ administered SkM through the coronary arteries in a rat model of dilated cardiomyopathy induced by doxorubicine and found, 4 weeks after transplant, discrete loci positively stained for skeletal MHC in cell-transplanted hearts which was associated with an improvement in cardiac function.

Injection of SkM has routinely been applied directly into the myocardium. Although this system has the advantage that it guarantees that the cells are delivered to the ischaemic area, from the clinical point of view it has the disadvantage that it requires major surgery for patients. Although stem cells can be delivered by intracoronary access and even retrograde, direct injection into the coronary arteries could have a risk of coronary embolism because of the size and adhesive characteristics of SkM.¹⁴

We have recently compared the effect of endo-ventricular injection of SkM on cardiac function by percutaneous access in comparison with direct intramyocardial injection.¹⁵ A large animal model of chronic MIs was induced in Goettingen minipigs by insertion of a coil (Vortx Vas Occlusion Coil 2 x 3 mm, Boston Scientific Iberica SA, Barcelona, Spain) to the intermediate branch of first or second marginal artery. Interestingly, similar levels of cell engraftment at 3 months post-transplant were observed in the groups of animals treated with SkM. There was a statistically significant improvement in LVEF in both cell-treated groups when compared with control animals that were treated with media, indicating that delivery of SkM by either method provides similar benefit in a chronic model.¹⁵ These effects were also associated with a significant increase in vasculogenesis and reduced fibrosis in animals treated with SkM. As we will discuss latter, these can be some of the mechanisms implicated in the potential beneficial effect of cell therapy with SkM in ischaemic disease.

	Mechanisms of cardiac repair by skeletal myoblasts

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
A large amount of preclinical studies indicate that functional improvement after transplantation of SkM is unlikely to result from newly generated, beating cells. With the exception of the recently described skeletal precursors of cardiomyocyte cells (Spoc) isolated from muscle of mice that have demonstrated their potential to differentiate into beating and functional cardiomyocytes both in vitro and in vivo,¹⁶ the general concep is that SkM do not differentiate into cardiomyocytes.⁹ As cell-based approaches can improve function of the injured or failing heart independent of true regeneration, the question is how SkM may contribute to improved cardiac function?

The paracrine hypothesis remains the most plausible explanation. SkM as well as other types of stem and progenitor cells have been described to release a number of cytokines and growth factors that participate in processes such as angiogenesis, inflammatory reaction, migration and chemotaxis, matrix remodelling, cell proliferation, or inhibition of apoptosis.¹⁷ Thus the benefit from (stem) cell transplantation is likely to be related to enhanced angiogenesis/arteriogenesis,¹⁸ changes in ventricular remodelling,¹⁴ or to cytokine-mediated effects that enhance survival of cardiac cells,¹⁷ or even recruitment and induction of proliferation of endogenous stem cells.^19,20 As an example, we have recently demonstrated in a swine model of chronic MI that transplantation of autologous SkM despite limited engraftment induces a very significant increase in angiogenesis and vasculogenesis, and a decreased fibrosis due not only to a reduction in the amount of collagen deposition, but also to a change in the profile of collagen being deposited favouring a decrease in the ratio of collagen I/III which would limit the diastolic dysfunction of the heart.¹⁵

In a very elegant study, using a cre-lox reporter system, Reinecke et al.²¹ demonstrated that SkM fuse with host cardiomyocytes in vivo. Although this could be another mechanism contributing to improve cardiac function by rescuing damaged cardiomyocytes, the limited number of fusion events detected in this model does not support a significant role of cell fusion in improvement of cardiac function after SkM transplant.

	Skeletal myoblast transplant and cardiac arrhythmias in animal models

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
The most daring complication of SkM transplant in humans with chronic MI is the potential for inducing cardiac arrhythmias.²² Preclinical data based on animal models of MIs did not anticipate the potential for development of arrhythmias after SkM transplant. However, initial clinical trials detected an unexpected high incidence of ventricular tachycardia and even sudden death in patients undergoing transplantation of SkM^23,24 which blunted the interest in this type of therapy. The development of arrhythmias has not been consistent in every study as some clinical trials have not been associated with a significant incidence of arrhythmias^25,26 and even a recently completed phase II randomized trial suggests that there is not a statistically significant increase in the incidence of arrhythmias in the myoblast-transplanted group in comparison with the control group (Menasche, personal communication). The reasons for the discordant results are unclear, as it is whether the lack of arrhythmias in some studies may be due to a more aggressive prophylaxis or to differences in cell culture (for instance, the lack of xenogeneic proteins such as foetal calf serum).²⁷

Recent in vitro and in vivo animal studies have provided some new insights into the potential mechanisms of arrhythmias after SkM transplant.^28–30 Using a rat model of MIs and by performing programmed electrical stimulation using standard protocols, Fernandes et al.²⁸ reported an increased inducibility of ventricular arrhythmias in myoblast-injected rats compared with controls. This was evident 2 and 3 weeks after myoblast transplantation and declined thereafter. However, the incidence of spontaneous events was not increased in the myoblast-treated animals, suggesting that myoblast transplantation into the infarcted myocardium forms a substrate for ventricular arrhythmias although it does not per se induced arrhythmias. Interestingly, it seems that the arrhythmogenicity of different cell types may be variable and even in some cases cell transplant may provide a beneficial effect like in the case of MSC.³¹

A number of mechanisms have been implicated in the increased incidence of arrhythmias after SkM transplant: (1) SkM express growth factors, such as insulin-like growth factor-1, promotes myocyte hypertrophy, and induces alterations in the action potential duration,³² (2) SkM show a different pattern of action potentials that cardiomyocytes can predispose to re-entry circuits or enhanced automaticity, key mechanisms of ventricular arrhythmias,^30,33 and (3) SkM do not express gap junctions, so they are isolated from the surrounding cardiomyocytes leading to arrhythmias as has been suggested by a recent in vitro study.³⁰

Overall, based on preclinical as well as clinical data available, it is reasonable to assume that SkM increases the arrhythmogenicity in an already pro-arrhythmogenic substratum which supports the use of prophylactic measures to prevent this complication associated with cell transplant as well as the continuous evaluation of the risk.

	Future directions (how to improve the results of cell therapy with skeletal myoblasts)

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
A major limitation of cell transplantation remains death of the grafted cells. Attrition of more than 90% of the transplanted cells has been reported within the first 48 h following their intramyocardial implantation^34,35 and is related to a number of factors including the inflammatory reaction triggered by needles, oxidative stress,³⁶ apoptosis, and ischaemia related to the poor vascularization of scar. This major loss of grafted cells is likely to seriously diminish the efficacy of the procedure as the functional benefit expected from myoblast transplantation is tightly related to the number of injected myoblasts.³⁷ A number of approaches have been studied in order to improve engraftment and/or survival of transplanted SkM. It maybe an oversimplification to assume that simply by increasing the number of cells injected will address the issue of graft survival, so the importance of other approaches aimed to enhance graft survival are more likely to yield positive results.

Strategies to improved cell engraftment have been based on the mechanisms involved in cell attrition. SkM have been transplanted after being preconditioned with antioxidants (diazoxide),³⁸ anti-inflammatory drugs (anti-IL1-beta antibodies),^34,36 or agents that induced cell protection as cold or heat shock proteins.^35,39 Although these studies have shown some improvement in engraftment, this has been quite limited (two- to four-fold). Other studies have focused on optimizing the vascular supply to reduce the ischaemic component of cell death. Increased angiogenesis can be obtained by co-injections of angiogenic growth factors (vascular endothelial growth factor [VEGF], hepatocyte growth factor)^18,40,41 or transplantation of transfected myoblasts over-expressing either one of these factors or a master gene such as hypoxia-inducible factor 1⁴² which regulates the expression of a wide array of genes involved in angiogenesis. These studies suggest that cell delivery of growth factors (using viral vectors) or alternatively by controlled released systems⁴¹ instead of direct administration of the cytokine may yield better functional results.¹⁸ A note of caution has been raised by a recent study in which transplantation of VEGF expressing SkM in a rat model of MIs was associated with the development of vascular tumors.⁴³

Stimulating the recruitment of cells with the potential to facilitate vasculogenesis or angiogenesis has also been reported to be successful either by co-transplantation of myoblasts and bone marrow cells (combined cells) or by stimulating homing of cells with angiogenic potential such as endothelial progenitor cells. It has been reported that transplanted SkM have the ability to establish signalling for stem-cell homing through the expression of the potent chemoattractant stroma-derived factor (SDF)-1.⁴⁴ This factor acts as a ligand for the receptor CXCR4 expressed by some bone marrow cells as well as by SkM. Circulating bone marrow cells should thus increase their homing to myocardial foci of high SDF-1 concentration and their capacity to locally increase angiogenesis, most likely through the release of angiogenic growth factors⁴⁵; this, in turn, is hoped to enhance myoblast survival and post-engraftment left ventricular function. The use of biodegradable scaffolds seeded with SkM can also exerts a protective effect on cell death.⁴⁶ Recent studies using a bioactive fibrin scaffold or collagen glue with SkM has demonstrated a significant improvement in cell engraftment associated with increasing angiogenesis leading to decreased remodelling and a better preservation of heart function.^47,48 Finally, the use of repeated injections has also been suggested to result in increasing engraftment and improvement in cardiac function in comparison with the same dose of cells administered in a single procedure.⁴⁹

	Conclusions

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
Despite all the caveats and limitations associated with cell therapy for cardiac diseases and more specifically SkM, and the lack of complete knowledge of the mechanisms involved in the potential benefit of these therapies, we believe that there is sufficient information as to continue investigating these therapies. Along with well-designed clinical trials focused on specific questions, bench research aimed to understand the mechanisms by which cells may exert their effect and to improve cell-delivery systems and cell engraftment is worth pursuing and should lead to generation of new cell-based therapies for patients with cardiac diseases.

	Funding

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
This work was supported by grants from Fondo de Investigaciones Sanitarias PI042125, PI050168, ISCIII-RETIC RD06/0014, FEDER (INTERREG IIIA), and the UTE project CIMA.

Conflict of interest: none declared.

	Acknowledgements

Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 
The work described in this Review was supported by grants from Fondo de Investigaciones Sanitarias PI042125, PI050168, ISCIII-RETIC RD06/0014, FEDER (INTERREG IIIA) and the "UTE project CIMA".

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Top Abstract Introduction Cardiac repair with skeletal... Mechanisms of cardiac repair... Skeletal myoblast transplant and... Future directions (how to... Conclusions Funding Acknowledgements References

 

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