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Cellular Cardiomyoplasty: What Have We Learned?

Department of Surgery, James H Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA

Race L Kao, PhD, Tel: +1 423 439 8803 Fax: +1 423 439 8750 Email: kao{at}etsu.edu, Department of Surgery, James H Quillen College of Medicine, East Tennessee State University, Johnson City.

	ABSTRACT

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Restoring blood flow, improving perfusion, reducing clinical symptoms, and augmenting ventricular function are the goals after acute myocardial infarction. Other than cardiac transplantation, no standard clinical procedure is available to restore damaged myocardium. Since we first reported cellular cardiomyoplasty in 1989, successful outcomes have been confirmed by experimental and clinical studies, but definitive long-term efficacy requires large-scale placebo-controlled double-blind randomized trials. On meta-analysis, stem cell-treated groups had significantly improved left ventricular ejection fraction, reduced infarct scar size, and decreased left ventricular end-systolic volume. Fewer myocardial infarctions, deaths, readmissions for heart failure, and repeat revascularizations were additional benefits. Encouraging clinical findings have been reported using satellite or bone marrow stem cells, but understanding of the benefit mechanisms demands additional studies. Adult mammalian ventricular myocardium lacks adequate regeneration capability, and cellular cardiomyoplasty offers a new way to overcome this; the poor retention and engraftment rate and high apoptotic rate of the implanted stem cells limit outcomes. The ideal type and number of cells, optimal timing of cell therapy, and ideal cell delivery method depend on determining the beneficial mechanisms. Cellular cardiomyoplasty has progressed rapidly in the last decade. A critical review may help us to better plan the future direction.

Key Words: Adult Stem Cells • Heart Failure • Myocardial Infarction • Myocytes • Cardiac

	INTRODUCTION

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The scope of this review is adult autologous stem cells derived from skeletal muscle or bone marrow for cellular cardiomyoplasty. Although other types of stem cell from adipose tissue, cord blood, and other organs or tissues can also be used, skeletal muscle and bone marrow stem cells are commonly employed. Due to the huge number of publications relating to cellular cardiomyoplasty, only recent directly related publications are cited, with apologies for any omissions. For more in-depth information, several books and reviews are listed as excellent resources. This article will focus on the lack of regenerative capability of adult mammalian ventricular muscle cells, recent progress to overcome cell cycle arrest, and the existence of cardiac stem cells. Achievements using skeletal muscle and bone marrow stem cells are discussed. Future directions and possible improvements in cellular cardiomyoplasty are suggested. Cellular cardiomyoplasty is still at an early stage of development; with further improvement, a revolutionary change in the treatment of cardiovascular disease may occur.

	CARDIAC MYOCYTE TERMINAL DIFFERENTIATION AND MYOCARDIAL REGENERATION

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Ventricular muscle cells of adult mammals have been considered for more than half a century as terminally differentiated cells that have lost their ability to replicate to repair damage.^1–5 Shortly after birth, cardiac myocytes switch from hyperplasia to hypertrophy; growth of the heart is accomplished by hypertrophy of heart muscle cells and hyperplasia of non-muscle cells. Injury to the heart consistently results in the formation of scar tissue, further attesting to the lack of regenerative capability of mammalian myocardium. Following myocardial infarction (MI), necrotic, apoptotic, and stunned (hibernating) myocardium leads to an early decrease in ventricular function. Infiltration of neutrophils and accumulation of macrophages, followed by the formation of granulation tissue and scar tissue, result in infarct expansion and ventricular remodeling that progresses to ventricular dysfunction and congestive heart failure (CHD). It is estimated that 15.8 million Americans suffer from coronary heart disease, with 7.9 million heart attacks each year.⁶ There are also >5 million patients with CHD in the USA.⁶ Cellular cardiomyoplasty, on which we started work 2 decades ago by implanting autologous stem cells to treat MI and CHD, has gained significant interest in experimental and clinical studies.^1,7–19 Cellular cardiomyoplasty may be an effective treatment for patients with MI or CHD.^1,7,8,20

The mammalian cell cycle is a highly conserved and regulated process that can be divided into gap (G₀, G₁, G₂), DNA synthesis, and mitosis phases. The cyclins, cyclin-dependent kinases, and a number of activators, inhibitors, and regulators orchestrate the cell cycle.²¹ Withdrawal of the cardiac myocyte from the cell cycle during early postnatal life is associated with changes in the expression of many cell cycle regulatory molecules. Adult transgenic mice expressing cyclin D2 under the regulation of cardiac myosin heavy-chain promoter exhibit a high rate of cardiomyocyte DNA synthesis under baseline conditions.²² After cardiac injury, cyclin D2 transgenic mice show persistent cell cycle activity and infarct regression. Following left coronary artery occlusion, both control and transgenic mice had similar cardiac functional impairment at 7 days. Transgenic animals exhibited a progressive and marked increase in cardiac function at 60 and 180 days, which correlated with the presence of newly formed myocardial tissue.²³ Cardiac-specific p38 knockout mice showed >90% increase in neonatal cardiomyocyte mitoses, and inhibition of p38 in adult cardiomyocytes significantly increased karyokinesis and cytokinesis.^24,25 Mice with constitutive expression of cyclin A2 in the myocardium elicited a regenerative response after MI, with preserved and enhanced cardiac function.²⁶ Potential beneficial mechanisms of cyclin A2 expression were attributed to cultured transgenic cardiomyocytes demonstrating cytokinesis and proliferation of side population cells.²⁷ Cardiomyocyte cell cycle activation may provide alternative treatment for MI and CHD.

The paradigm that adult mammalian ventricular myocardium cannot regenerate functional myocytes has been challenged recently by the identification of cardiac stem cells. The possible existence of stem cells or progenitor cells in neonatal rat myocardium was suggested in 1996.²⁸ So far, several distinct types of stem cell or progenitor cell, such as side population cells, c-kit⁺ cells, Sca-1⁺ cells, and is l1⁺ cells have been identified.^29–38 Recently, cardiosphere-derived heart stem cells have been isolated from mammalian ventricular myocardium.^39–42 They are capable of long-term self-renewal and differentiation into myocytes, smooth muscle cells, and endothelial cells, under both in-vitro and in-vivo conditions. The clonogenic and myocardial regeneration potential of heart cells were suggested in recent reviews. Heart cells from cardiospheres can be isolated from experimental animals and humans, with long-term self-renewal, clonogenic, and multipotential.^39–48 However, functionally significant myocardial regeneration has not been documented in diseased or injured heart. Adult mammalian myocardium lacks adequate endogenous regenerative capability, and cellular cardiomyoplasty seems a viable approach to reconstitute damaged myocardium and prevent CHD.

	CELLULAR CARDIOMYOPLASTY USING SATELLITE CELLS (MYOBLASTS)

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Most tissues and organs of adult mammals contain minor populations of primitive stem cells and progenitor cells for ongoing tissue maintenance and regeneration. Adult stem cells are undifferentiated cells residing in differentiated tissues, capable of self-renewal and proliferation to produce differentiated cells. Adult stem cells can yield specialized cell types of the tissue from which they originated, and are capable of developing into cell types that are characteristic of other tissues (plasticity). Self-renewal and plasticity of adult stem cells have been well established in recent years.^49–51 Cell therapy has emerged as a strategy for the treatment of many human diseases.^52–54 The aim of cellular cardiomyoplasty is to replace, repair, or enhance the biological function of the damaged or failing heart.^55–57

Since we initiated cellular cardiomyoplasty in 1989, our successful outcomes have been confirmed by others.^1,7,8,58,59 Clinical cellular cardiomyoplasty was first performed by Menasché’s group in 2000.⁶⁰ Since then, a number of small-scale uncontrolled clinical trials have been reported by different groups. Skeletal muscle satellite cells (myoblasts) have the advantages of autologous availability, capacity to proliferate in vitro to a vast quantity, lack of tumor-igenicity, more commitment to myogenic differentiation, and high resistance to ischemia/hypoxia, allowing good survival and engraftment after transplantation. Early clinical applications produced highly encouraging results, summarized in recent reviews.^{1,9–11,61–63} Although feasibility, safety, improved survival, and encouraging outcomes have been observed in long-term follow-up studies, definitive long-term efficacy requires large-scale placebo-controlled double-blind randomized trials, such as the MAGIC study.^60,6,64 Unfortunately, after 120 patients, myoblast transfer did not show significant improvement of regional or global left ventricular function, beyond that in controls.⁶⁴ However, the high-dose cell group demonstrated a significant decrease in left ventricular end-systolic and end-diastolic volumes compared to the placebo group. The CAUSMIC trail is a phase I open randomized study including 23 patients, with safety and feasibility as primary endpoints, and efficacy as a secondary endpoint.⁶⁵ Improvements in myocardial viability, quality of life, and heart function warrant the phase II study of 165 patients. In a recent report of the SEISMIC phase II open-label randomized controlled multicenter trial, the benefit of cell implantation was also clearly documented. This leads to the MARVEL trial (phase II/III double-blind randomized placebo-controlled multicenter study) that will involve 330 patients to better elucidate the possible benefit of muscle-derived stem cells in cellular cardiomyoplasty.

	CELLULAR CARDIOMYOPLASTY USING BONE MARROW-DERIVED CELLS

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Adult bone marrow contains multiple cell populations of differentiated and undifferentiated cells (stem cells), such as hematopoietic and mesenchymal stem cells, and endothelial progenitor cells. A mixed population of bone marrow cells, rather than purified stem cells, is commonly used for cellular cardiomyoplasty.^66–68 The safety and ease of obtaining the cells, observation of new muscle tissue formation, improvement of contractile function, enhancement of local perfusion, and prevention of remodeling and deterioration of the injured heart have been documented in experimental animal studies.^1,16,20,69

Despite a lack of clear understanding of beneficial mechanisms, phase 1 clinical studies have shown the feasibility and safety of the procedure, with encouraging functional improvements.^1,9,14,18,20 Treatment-control trials (TOPCARE-AMI, IACT, BOOST, MAGIC Cell-3-DES, ASTAMI) have been reported, but the number of patients involved is relatively small.^70–75 Randomized placebo-controlled trials with small- to medium-sized samples have also been reported.^76–79 The double-blind placebo-controlled FINCELL study involved 78 patients (39 per treatment), and demonstrated significant improvement in ejection fraction after treatment with mononuclear bone marrow cells.⁶⁵ The HEBE trial completed only a pilot study, with safety, feasibility, and positive outcomes to support the recruitment of 200 patients.^80,81 The MYSTAR study has not reported its findings.⁸² So far, improved left ventricular ejection fraction, reduced heart enlargement, significantly improved blood flow reserve, lower rates of mortality, MI, and hospitalization due to CHD all indicate the efficacy of cellular cardiomyoplasty using bone marrow cells. The beneficial mechanisms and factors regulating the differentiation of bone marrow stem cells into heart muscle cells are under current investigation by many groups.

Although bone marrow mesenchymal stem cells, bone marrow mononuclear cells, and circulating progenitor cells represent different population of cells, recent meta-analyses combined them under the term adult or autologous bone marrow-derived cells.^83–85 Representing 500–1,000 patients, bone marrow cell-treated groups had significantly improved left ventricular ejection fraction, reduced infarct scar size, and decreased left ventricular end-systolic volume and as compared to controls. Lower rates of recurrent MI, death, re-hospitalization for CHD, and repeat revascularization are additional favorable outcomes. Greater cell numbers seem to be associated with more improvement, further supporting the notion that the delivered cells are producing the beneficial effects.

	WHAT HAVE WE LEARNED?

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FEASIBILITY AND SAFETY
The technical feasibility and safety of cellular cardiomyoplasty is well established, long-term engraftment of the transplanted cells is clearly documented, and efficacy in restoring ventricular function is unambiguously proved.^{1,9–20,61–65} Decreased scar tissue, better blood perfusion, enhanced metabolism, augmented regional function, improved global function, prevention of infarct expansion, minimized remolding, prevention of cell death, and regeneration of viable myocardium are commonly observed beneficial outcomes.^1,20,84 However, the possible mechanisms listed below, which might lead to these favorable outcomes, lack general consensus among investigators. (1) Development of new tissue (muscle) from the implanted cells: new tissue will increase wall thickness and improve compliance or provide a scaffold effect. New viable cells might rescue damaged cells or modify the extracellular matrix. If new muscle cells are developed and contract in synchrony with existing cardiomyocytes, either by formation of functional gap junctions or by cell fusion, improved pump function can be expected. (2) Angiogenesis and/or vasculogenesis: stem cells have the potential to form smooth muscle and endothelial cells for the formation of new blood vessels. They can release angiogenic factors to induce angiogenesis or vasculogenesis. With improved perfusion, remolding can be minimized or reversed, and hibernating or at-risk cells can be rescued. (3) Paracrine and endocrine effects: the release of cytokines, growth factors, and angiogenic factors can improve blood perfusion, enhance cell growth, promote cell division, and mobilize, activate, and allow homing of stem cells to the site. (4) Immune and inflammatory responses: other than releasing cytokines and growth factors, certain stem cells have proved to have antiinflammatory and immunosuppressive effects. After transplanting stem cells into an injured heart, a significant fraction of the cells are lost by apoptosis.^1,9,86 Apoptotic cells can induce antiinflammatory and immune suppressive effects to prevent infarct expansion and ventricular remodeling. So far, every type of cells used for cellular cardiomyoplasty has generated a positive outcome.^{1,9,18,46,62,87,88} This makes the identification of a specific beneficial mechanism very difficult. In addition, reproducible and consistent generation of a substantial quantity of cardiomyocytes from implanted cells has not been achieved. Only if progenitor cells can differentiate into significant amounts of cardiomyocytes with and having electromechanical coupling with other heart muscle cells, can optimal outcomes of cellular cardiomyoplasty be expected.

CELL RETENTION AND ENGRAFTMENT
The rapid and significant loss of implanted cells after cellular cardiomyoplasty can be attributed to biological and mechanical losses. Different routes and methods of cells delivery as well as their retention and engraftment have been summarized by an excellent recent review.⁸⁹ Cellular washout after intramyocardial delivery has been suggested;⁹⁰ however, the study of Teng and colleagues⁹¹ using microspheres of similar size to the cells proved the mechanical loss of cells to be 90% or more within 10 min of administration. Using gelling agents (Pluronic F127 or Matrigel) as vehicles reduced the immediate loss of microspheres, but did not improve retention at 20 min after intramyocardial injection.⁹² Significantly less cell retention was observed after vascular administration, although this could be easier than intramuscular delivery, greater systemic exposure might produce undesired complications.⁸⁹ Increased delivery efficiency not only optimizes the targeted efficiency but also minimizes the undesired systemic exposure. Although the exact beneficial mechanisms of cellular cardiomyoplasty are unknown, higher cellular retention is believed to produce a better outcome. Improved cell retention and engraftment might augment the results of cellular cardiomyoplasty.

To determine retention and engraftment, assessment and identification of the implanted stem cells is crucial. Early studies used radioisotope, LacZ, GFP, DAPI (4',6-diamidino-2-phenylindole), microspheres, BrdU (5-bromo-2'-deoxyuridine), or DiI (dialkylcarbocyanine), but they all suffered limitations.⁸ Using the Cre/Lox donor/recipient pair system or the X and Y chromosome fluorescence in-situ hybridization method, differentiation or fusion of donor cells was unambiguously identified.^93–96 Obviously, using male donor cells transplanted into a female recipient will be required for an X and Y chromosome study that can be easily accomplished using syngeneic experimental animals. For a clinical study, with the development of universal donor cells, the fluorescence in-situ hybridization method can also be applied.⁹⁷

DIFFERENT STEM CELLS FOR CELLULAR CARDIOMYOPLASTY
Using experimental animals, skeletal muscle satellite cells were better than bone marrow-derived cells or there were similar beneficial effects for both cells.^98–100 After evaluating all experimental and clinical publications using skeletal myoblasts and bone marrow stem cells, a recent review concluded that further studies on a longer-term basis will be needed to make any decision.¹⁰¹ Other than comparing bone marrow versus circulating progenitor cells in a controlled crossover study, a direct comparison of different stem cells in a single clinical center has not been reported.¹⁰² Using in-vivo and in-vitro cardiomyocyte differentiation as well as regional and global cardiac functional improvement to evaluate different types of cells, current experimental and clinical studies suggest that the beneficial outcomes of cellular cardiomyoplasty are independent of cell type used.^18,88 We must take one step back to resolve cell purity (preparation containing only the desired type of cell), viability, retention, and engraftment before any meaningful study to compare different types of stem cell for cellular cardiomyoplasty can be performed.

A longer-term comparison will also be necessary based on the BOOST trial that observed significant improvement at 6 months but no difference at 18 months for the cell group vs. control group.⁷² This suggests that satellite cells should perform better than bone marrow stem cells due to the beneficial effects remaining for 4 years or longer.^60,63 However, long-term (1-year) beneficial outcomes using bone marrow stem cells were observed by the TOPCARE-AMI and REPAIR-AMI trials that were different from the BOOST and ASTAMI trials and another report.^{70,72,76,78,79} One major difference between these studies was attributed to the solutions used for storing bone marrow stem cells.¹⁰⁴ TOPCARE-AMI and REPAIR-AMI trials used culture medium with autologous serum, while the other trials used saline or saline with serum or plasma.^{70,72,76,78,79} Storing bone marrow stem cells in saline plus plasma resulted in functional impairment of the cells.¹⁰³ Again the viability, purity, and retention of the cells are critical issues needing be solved before a long-term study can be planned.

Each gram of ventricular muscle contains approximately 20 million myocytes. To replace the cardiomyocytes lost after MI, cellular cardiomyoplasty may need to produce 1 billion heart muscle cells. Although robust proliferation of stem cells under culture conditions is commonly observed, after intramyocardial implantation, the proliferation potential seemed limited in most studies. Even with a poor retention rate, if the implanted stem cells proliferate without overgrowth, a few stem cells theoretically can grow into billions of cells in a reasonable time frame.

OPTIMAL TIME FOR CELL IMPLANTATION
Although the optimal time after MI for cellular cardiomyoplasty has not been established in a clinical study, performing the treatment at a similar time after disease onset will allow more direct comparison between different stem cells.^1,9,104,105 Cellular cardiomyoplasty procedures all suffer from very low cell retention and massive cell death after treatment, irrespective of the type of stem cell studied.^86,89,92,106 Multiple stem cell treatments at different time intervals may significantly improve engraftment and the outcomes of cellular cardiomyoplasty. Based on pathological changes after MI and experimental studies, 2 to 4 weeks after acute MI seems to be the optimal time for cell therapy.^107,108 However, clinical outcomes showed that administration of stem cells shortly after acute MI or into an old infarct produced similar beneficial outcomes, and cell therapy may be independent of time to treatment.

Most stem cell preparations applied in studies contained a mixed population of cells. Purified stem cells have the potential for higher retention and survival rates without the complications of non-stem cells. Purified stem cells may be required in future studies. Muscle samples of 5–10 g are recommended for satellite cell isolation. Smaller samples make isolation difficult and require longer culture time to yeild sufficient satellite cells. A long culture time is undesirable for any stem cells, with the potential for genetic modification and higher non-stem cell contamination. Most studies compared 6-month follow-up results, but longer follow-up is necessary, especially in view of the lesson learned in the BOOST trial with a significant improvement at 6 months but no difference at 18 months for the cell group vs. control group.

MYOCARDIAL INFARCTION AND HEALING
With so many unanswered questions, it is wise to take a step back and review the new information on molecular and pathological changes after MI to delineate possible beneficial mechanisms of cellular cardiomyoplasty. After acute MI, the healing process can be divided into 4 phases: cardiomyocyte death, acute inflammation, tissue granulation, and remodeling or repair.¹⁰⁷ It is well known that MI is an inflammatory disease, and there is compelling evidence that the innate immune response plays an important role in myocardial ischemia-reperfusion injury and CHD.^107,19–113 Ischemia-reperfusion significantly increases tumor necrosis factor, interleukins-1, -6, and -8, interferon, and intercellular adhesion molecule-1 gene expression in myocardium.^114–116 These pro-inflammatory and immunoregulatory cytokines appear to be directly involved in the progression of myocardial ischemia-reperfusion injury, myocardial dysfunction, ventricular remodeling, CHD, and cardiac hypertrophy.^117–120

Toll receptors are an ancient and evolutionarily conserved receptor family that regulate innate immunity, inflammation, and antimicrobial host defense.^121–123 In 1997, human homologues of Toll, designated Toll-like receptors (TLRs) were discovered.¹²⁰ To date,>10 TLRs have been identified in mammals.^121,122 Mammalian TLRs are characterized by extracellular leucine-rich repeat motifs and a cytoplasmic Toll homology domain similar to that of the interleukin-1 receptor family of proteins, designated the Toll/interleukin-1 receptor homology domain. The interleukin-1 receptor/TLR family shares a common signaling pathway leading to nuclear factor-kappa B (NFB) activation (Figure 1).¹²² Mammalian TLRs play a critical role in induction of innate immune and inflammatory responses.^121–124 TLRs have been identified in human stem cells that mediate stress and immune modulating responses.¹²⁵

View larger version (66K): [in this window] [in a new window]   Figure 1. Toll-like receptor signaling pathway and PI3K/Akt signaling pathway. Activation of Toll-like receptors (TLR) results in activation and nuclear translocation of nuclear factor-B (NFB) which binds to specific DNA motifs in or near the promoter region of immune and/or inflammatory genes to produce immunoregulatory and proinflammatory mediators. PI3K/ Akt signaling pathways are involved in regulating cellular proliferation and survival.

Stimulation of TLR4 induces cardiac myocyte apoptosis. The contribution of cardiac myocyte apoptosis to myocardial injury has been well documented.^138,139 TLR4 activation contributes to myocardial injury; whether TLR4 is involved in cardiac myocyte apoptosis following myocardial ischemia-reperfusion is unclear. Recent evidence suggests that TLRs can function as death receptors.^140,141 Overexpression of TLR4 results in apoptotic cell death, while transfection of dominant negative Fas-associated death domain (FADD) protein significantly inhibits TLR4-mediated cell death (Figure 2).¹⁴² These data suggest that TLR4-mediated apoptosis may signal through a FADD-dependent pathway. Toll-IL-1 receptor-domain-containing adapter-inducing IFN-beta (TRIF) is another TLR-adaptor protein, and both TLR3 and TLR4 can transduce their signals via TRIF which is a MyD88-independent pathway.¹⁴³ TRIF-induced apoptosis occurs through activation of the FADD-caspase-8 axis.¹⁴⁰ In-vivo data have shown that LPS-induced splenic dendritic cell apoptosis depends on TLR4, TRIF, and MyD88 adaptor proteins.¹⁴⁴ We have shown that overexpression of TLR4-sensitized cells to serum deprivation-induced apoptosis, while transfection of dominant negative FADD into the cells significantly reduced apoptosis.¹⁴¹ We observed that cardiac myocyte apoptosis was significantly reduced in TLR4 knockout mice compared to wild-type mice.¹³⁴ Collectively, these data indicate that TLR4 may mediate apoptotic signaling that contributes to cardiac myocyte apoptosis following myocardial ischemia-reperfusion. However, how TLRs mediate stem cell apoptosis after their implantation is unknown.

View larger version (54K): [in this window] [in a new window]   Figure 2. Toll-like receptor 4 (TLR4) transmits apoptotic signaling through the interaction of MyD88 with Fas-associated death domain (FADD), causing inactive procaspase-8 to become active caspase-8, resulting in stimulating effector caspase signaling and induce apoptosis.

Because innate immune and inflammatory responses are involved in myocardial ischemic injury, investigation of the innate immune modulation and antiinflammatory activities of stem cells during cellular cardiomyoplasty may reveal the beneficial mechanisms. Adult tissues have been used to isolate stem cells that show plasticity, escape immune recognition, and inhibit immune responses. Adult stem cells can easily proliferate to vast numbers and be applied to inhibit immune responses by suppressing T and B cell proliferation, inducing T regulatory cells, modulating B cell and dendritic cell functions, and to treat transplant rejection.^148–153 They do not induce lymphocyte proliferation and are not targets for cytotoxic lymphocytes or natural killer cells. No adverse events during or after adult stem cell transplantation have been observed, and no ectopic tissue formation has been noted.^149–152 Other than paracrine or endocrine effects, anti-proliferative, antiinflammatory, and immunomodulatory effects of stem cells to prevent infarct expansion and remodeling may be the major benefits.^{1,125,149,154}

STEM CELLS FOR IMMUNE MODULATION AND ANTIINFLAMMATION
Multicellular organisms maintain a proper balance of viable, apoptotic, and necrotic cells. The clearance of apoptotic cells is carried out by macrophages, neutrophils, and dendritic cells (especially immature dendritic cells) that can result in either immunosuppressive or pro-stimulatory effects.^155–158 When cells are dying by apoptosis, they will be phagocytosed by mechanisms so as not to incite inflammatory or immune reactions but antiinflammation and tolerance. The induction of pathogenic immune responses may be dependent on the immune system receiving "danger" signals resulting from tissue damage. Immature dendritic cells express receptors of apoptotic cells for self-tolerance, and Toll-like receptors for pathogen-related molecules.^155–158 Dendritic cells that capture apoptotic cells in the steady state mediate peripheral tolerance to self-antigens. The regulatory properties of dendritic cells include induction of T-cell anergy, apoptosis, immune ignorance, and generation of T regulatory (suppressor) cells can induce self-tolerance and immunosuppression.^155–161 The effect of apoptotic cells can be long-lasting and relatively stable. After transplanting stem cells into an injured heart, a significant fraction of the cells are lost by apoptosis.^1,86,106 The apoptotic cells can induce antiinflammatory and immunosuppressive effects to prevent infarct expansion and ventricular remodeling, major benefits observed after cell therapy.

If antiinflammatory and immunosuppressive effects are the primary beneficial mechanisms of cellular cardiomyoplasty, this may partially explain why different kinds of stem cells and different times of cell treatment (after acute MI or an old infarct) resulted in similar favorable outcomes.^1,154 Stem cells can mediate immune suppression and antiinflammatory effects through secreted soluble factors and contact-dependent mechanisms.^149,150 More importantly, mesenchymal stem cells can exert antiinflammatory effects even at the site of inflammation (similar to after MI).¹⁵⁰ Since a significant fraction of the stem cells are lost by apoptosis after cellular cardiomyoplasty, and apoptotic cells can have long-lasting effects, a major benefit of cell therapy may derive from immune modulation and antiinflammation effects.

	FUTURE DIRECTIONS OF CELLULAR CARDIOMYOPLASTY

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Skeletal muscle in mammals can regenerate efficiently, while the regenerative capacity of myocardium is grossly inadequate to compensate after injury. Embryonic stem cells are totipotent cells that have the capability to differentiate into any type of cell in the body. However, their application in regenerative medicine is limited due to ethical concerns, formation of teratoma, and possible rejection after utilization.¹⁶² Adult stem cells are pluripotent or multipotent cells that have the advantage of an autologous source without ethical and cancer formation concerns. Recently, the induction of pluripotent stem cell lines from adult cells has been successfully achieved in different laboratories.^163–168 This accomplishment will clearly avoid the ethical concern, while induction of cancer from these cells and immune rejection after application remain uncertain. Using any type of stem cell or progenitor cell, one major limitation needing to be overcome is directing the cells to differentiate into the desired type to repair, restore, or augment the function of an ailing organ.

True cardiomyocytes derived from implanted stem cells are infrequent; therefore, directing differentiation of stem cells into heart muscle cells can be beneficial. Recently, human embryonic stem cells have been induced to form cardiomyocytes efficiently when cultured in defined media.^169,170 Activin and bone morphogenetic proteins induced differentiation of >30% of embryonic stem cells into cardiomyocytes, and they could be enriched to 80%–90% by density-gradient centrifugation. If the embryonic-like cells derived from adult cells can also be induced to form cardiomyocytes, they could be excellent cells for cellular cardiomyoplasty.^164–168 Bone marrow mesenchymal stem cells can be induced to form cardiomyocyte in vitro by 5-azacytidine treatment or co-culturing with neonatal cardiomyocytes.^171,172 Inducing stem cell differentiation into a cardiac lineage before implantation should allow better cardiomyocyte formation and possible functional improvement.

The outcomes of cellular cardiomyoplasty have been summarized in a number of excellent reviews.^{1,13,18,54,62,105,173} In general, there was a modest but significant improvement of ventricular function, resulting in a lower rate of recurrent acute MI, death, re-hospitalization for CHD, and repeat revascularization. Cell retention and engraftment rates are extremely low (normally <10%) and the proportion of cells lost by apoptosis is very high, so improved cell retention, engraftment, and viability should be the primary areas for improvement of cell therapy.^{1,86,89,92,106} Although approximately 1 billion myocytes will be need to replace the cells lost after MI, the new muscle cells formed from the implanted cells are far from this number. From the healing process of MI and an experimental study, 2 to 4 weeks after acute MI seems to be the optimal time for cell therapy.^107,108 However, the clinical outcomes of cellular cardiomyoplasty showed that administration of stem cells either shortly after acute MI or into an old infarct produced similar beneficial outcomes; thus cell therapy may be independent of time to treatment. The favorable results of cellular cardiomyoplasty seem independent of cell type used and time of administration, but moderately related to the number of cells given. These observations indicate immune modulation and antiinflammation may be the primary beneficial mechanisms of cellular cardiomyoplasty.

Universal donor stem cells can be prepared and stored in advance to have readily available homogeneous population of cells fully characterized with confirmed potential for cell therapy.⁹⁷ Human mesenchymal stem cells were implanted into sheep fetuses and found to survive without immunosuppression. These cells formed different differentiated cells of various organs, even after the development of immune competence.¹⁷⁴ When mouse mesenchymal stem cells were transplanted into the hearts of fully mature immune-competent adult Lewis rats, differentiation and survival of the mouse cells were observed without immunosuppression.^175,176 Allogeneic mesenchymal stem cells transplanted into the myocardium of an unrelated porcine model of MI resulted in engraftment, differentiation, and improvement of cardiac function.¹⁷⁷ For clinical application, allogeneic stem cells will be the obvious choice to avoid possible complications, and in April 2008, allogeneic mesenchymal stem cells were used in a patient subjected to cellular cardiomyoplasty.⁹⁷ All of these observations indicate the immunoprivilege and immunomodulatory capabilities of stem cells, and further support concept that immune modulation and antiinflammation may be the primary beneficial mechanisms of cellular cardiomyoplasty.

	REFERENCES

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Asian Cardiovasc Thorac Ann 2009; 17:89-101
© 2009 by SAGE Publications
DOI: 10.1177/0218492309104144

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