Ann Thorac Surg 2006;82:1549-1558
© 2006 The Society of Thoracic Surgeons
Reviews
Repair of the Damaged Heart by Bone Marrow Cells: From Experimental Evidence to Clinical Hope
Keng-Leong Ang, MRCS,
Lincoln Takura Shenje, MBChB(Hons), MS,
Lakshmi Srinivasan, FRCS,
Manuel Galiñanes, MD, PhD*
Cardiac Surgery Unit, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Clinical Science Wing, Leicester, United Kingdom
* Address correspondence to Dr Galiñanes, Cardiac Surgery Unit, Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, United Kingdom (Email: mg50{at}le.ac.uk).
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Abstract
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Heart failure remains the leading cause of death in developed countries in spite of improvements in medical and surgical treatments. However, recent observations in experimental studies that bone marrow cells may repair cardiac tissue have offered renewed hopes for the treatment of heart failure. This optimism is further supported by encouraging results from some clinical trials, although the degree of benefits, the underlying mechanisms, and the cell types involved remain to be elucidated. This review summarizes the relevant experimental and clinical studies supporting the use of bone marrow cells in myocardial repair, as well as the controversies and challenges encountered.
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Introduction
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Heart failure is the leading cause of morbidity and mortality in the Western world, affecting approximately 5 million people in the United States [1] and at least 10 million people in Western Europe [2]. Ischemic heart disease accounts for more than 50% of the reported cases of heart failure [3].
With the progression to end-stage heart failure, the therapeutic options are limited. Heart transplantation remains the treatment option that offers the best outcome in terminal failure [2]. However, transplantation is not widely available because of inadequate donor organs. Furthermore, owing to the need for life-long immunosuppression therapy to prevent organ rejection, and its associated complications, transplantation is not the ideal treatment.
Current therapy for heart failure is based on the traditional belief that the heart is unable to generate new cardiomyocytes to replace failing or dying myocytes, but instead adapts to new stresses by myocyte hypertrophy and cardiac remodeling. Recent studies have challenged this conventional view by demonstrating some degree of myocardial regeneration from the native heart tissue [4] as well as from extracardiac sources [5]. This observation has attracted immense interest to explore stem cell therapy as a potential treatment for cardiac disorders, as the native regenerative capacity may be inadequate in a pathologic heart.
Autologous bone-marrow–derived cells present an attractive source of stem cells, as their multilineage differentiation and multiorgan engraftment potential have been previously demonstrated [6]. They are also easy to harvest and prepare, simple to administer, and do not require additional immunosuppressive treatment. Furthermore, their application does not raise the ethical controversies associated with the use of embryonic stem cells. This review presents an overview of the different stem cell populations found in bone-marrow–derived cells, the current experimental evidence on how they may contribute to myocardial repair, and their applications in the clinical arena.
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Material and Methods
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Literature searches were performed using PubMed and its "related articles" function for English articles published up to April 2006, containing the associations of words "bone marrow," "stem cells," "cell transplantation," "myocardial regeneration," "neovascularization," "angiogenesis," "heart failure," and "ischemic heart disease." We also searched the relevant references from these articles.
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Overview of Different Stem Cells Within the Bone Marrow
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Traditionally, bone marrow was thought to contain two main groups of stem cells: hematopoietic stem cells and their supporting mesenchymal stem cells. It is now known that bone marrow also contains endothelial progenitor cells [7, 8] as well as a unique population of cells, called multipotent adult progenitor cells, with the capacity to generate all three germ layers [9, 10]. A summary of their main features is provided in Table 1.
As more is learned about bone-marrow–derived cells, their identification and classification become more crucial for understanding their physiologic and therapeutic relevance. However, this is challenging, as different stem cell populations contributing to different cell lineages may be present within an organ like the bone marrow, yet sharing similar markers. The lack of consistent data on stem cell lineage markers [11] further complicates this process. In the context of myocardial repair, it will be important to establish the contribution of different populations of bone-marrow–derived cells for improving cardiac function. It is also vital to dissect the mechanisms by which they improve cardiac function to optimize therapeutic interventions.
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Can Bone Marrow Cells Transdifferentiate Into Cardiomyocytes?
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One of the primary aims of bone-marrow–derived cell transplantation is to replenish dying myocytes by transdifferentiating into functional cardiomyocytes. For this, they have to acquire a cardiac morphology and express cardiac-specific markers and sarcomeric structures. They must demonstrate automaticity and coupling with host myocytes, and more importantly, work in a functional syncytium with the rest of the cardiac muscle. Whether bone-marrow–derived cells can differentiate into functional cardiomyocytes remains the most controversial and debated topic in this field at present.
In Vitro Studies
The earliest in vitro demonstration that bone-marrow–derived cells can differentiate into beating cells with cardiac phenotype was by treating immortalized murine mesenchymal stem cells with 5-azacytidine [12]; 30% of the cells formed myotube-like structures expressing cardiomyocyte specific genes. They also exhibited spontaneous beating and measurable action potentials. In addition, when these cells were implanted into myocardial scar tissue, they were associated with improvement in heart function [13]. Subsequently, it has been shown that cardiac-specific gene expression can also be induced in a population of human bone-marrow–derived multipotent adult progenitor cells expressing low levels of CD90, CD105, and CD117, as well as in blood-derived endothelial progenitor cells [14], when cocultured with live cardiomyocytes. Despite these favorable studies, reports of successful in vitro transdifferentiation of bone-marrow–derived cells into cardiomyocytes are scarce, suggesting that this process is complex and not easily reproduced for scalable therapeutic transplantation of cardiomyocytes. A closely regulated in vitro environment may be necessary for the occurrence of this transdifferentiation process, in which direct cell contact and paracrine cross talk with cardiomyocytes may also be essential [14, 15]. Even if transdifferentiation does occur in vitro, these findings still need to be substantiated by in vivo studies.
In Vivo Studies
Using immunofluoresence and confocal microscopy, it has been reported that lineage negative c-kit+ bone-marrow–derived cells can transdifferentiate into cardiomyocyte-like cells when injected into infarcted mice hearts [16], and contribute to the regeneration of as much as 65% of the damaged wall. The injected cells also developed endothelial and smooth muscle phenotypes, accompanied by an increase in neovascularization and overall cardiac function. However, similar experiments performed using bone-marrow–derived cells carrying reporter transgenes that would be switched on upon cardiac transdifferentiation of any cell have failed to reproduce these findings [17, 18]. Reporter gene failure was excluded by the use of several reporters and the successful expression of reporter genes in fetal-derived cardiac cells injected into the hearts of adult mice [17]. Instead, the transplanted cells adopted a mature hematopoietic phenotype in the myocardial scar, accompanied by a minor but statistically significant improvement in cardiac function [18].
One possible explanation for these discrepancies could be the difficulties in distinguishing myocyte nuclei from nonmyocyte nuclei by conventional confocal microscopy when the cells overlap. Even with the aid of advanced three-dimensional image reconstruction, the cytoplasm of adjacent myocytes can still be mistaken as a donor cell structure, and perceived as a transdifferentiation event. However, the differentiation of bone-marrow–derived cells was not demonstrated when cardiac reporter genes were used to track the fate of transplanted cells [17].
Another possible explanation is the phenomenon of cell fusion. Cell fusion occurs when a cell from one lineage fuses and adopts the phenotype of a host cell from a different lineage to form a heterokaryon, which can be mistaken for a transdifferentiation event. Bone-marrow–derived cell fusion with cardiomyocytes has been previously observed at a very low frequency after their transplantation in the heart using cre-lox technology [19, 20]. Nevertheless, false positive interpretation is also possible using this technology as a result of metabolic cooperation [21], if the cre recombinase from donor cells leaks into a recipient cell and activates the reporter gene without the occurrence of cell fusion. However, in these studies, the heterokaryons were shown to have double the complement of diploid DNA. While the observation of irreversible growth arrest after the fusion of bone marrow and Purkinje cells questions the contribution of this phenomenon in cell regeneration [22], other investigators have showed that fused cardiomyocytes were capable of cell cycle reentry [20]. Currently, the physiologic importance of fusion remains unclear, but its therapeutic potential appears limited. These conflicting results have stimulated considerable debate as to whether cardiomyocyte differentiation occurs, and whether the effects of bone marrow cells on myocardial repair are mediated through other mechanisms.
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Bone-Marrrow–Derived Cells and Cardiac Neovascularization
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Neovascularization describes the formation of new blood vessels, either from preexisting vascular network (angiogenesis) or through a de novo process from the circulating primitive endothelial precursors (vasculogenesis). In the damaged myocardium, enhanced neovascularization is believed to improve the natural repair and remodeling process by maintaining the perfusion to the remaining viable tissue in the watershed areas and limiting the extent of myocyte loss. It may also provide the necessary circulatory support to any newly formed cardiomyocytes.
The identification and isolation of cells participating in neovascularization from the bone marrow provides another means by which cellular therapy can enhance cardiac function. Endothelial progenitor cells from bone-marrow–derived cells have been shown to express endothelial phenotypes in vitro [8, 23, 24]. When a subset of endothelial progenitor cells was administered into animal models of myocardial infarction, it induced significant neovascularization within the ischemic regions, accompanied by reduced myocyte apoptosis, and improved overall cardiac function [25]. These cardioprotective effects and the degree of neovascularization have been found to be dependent on the numbers of cells delivered [26]. On microscopy, some of the administered endothelial progenitor cells were localized predominantly within the vessels of the peri-infarcted area, suggesting their direct participation in the neovascularization process. It is worth noting that certain populations of bone-marrow–derived cells within hematopoietic stem cells [16, 27], mesenchymal stem cells [9], and multipotent adult progenitor cells [10, 23] have also demonstrated similar capacity to express endothelial phenotypes in vitro and colocalize among capillaries of ischemic tissue.
However, as with studies investigating the ability of bone-marrow–derived cells to transdifferentiate into cardiomyocytes, there are concerns whether the above observations obtained using current microscopic techniques are robust enough as evidence for the functional incorporation by bone-marrow–derived cells into the vessel structures. These doubts are supported by a study in which no green fluorescent protein signals were detected within the growing vessels after green fluorescent protein positive bone-marrow–derived cells were transplanted into mice hindlimb ischemic model [28]. Instead, green fluorescent protein positive cells, in the form of fibroblasts, pericytes, and leukocytes, were found in the tissues around growing collateral arteries, coinciding with areas of high cytokine concentration. These findings suggest that bone-marrow–derived cells may have an important supportive role by interacting or optimizing the milieu for host tissue response to ischemic insults.
A supportive role of bone-marrow–derived cells in neovascularization is further substantiated by reports demonstrating the ability of different subpopulations of bone-marrow–derived cells [27, 29–31] to secrete angiogenic factors, such as vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, and angiopoietin-1. These factors play a vital role in neovascularization, and have been directly administered in models of ischemia with favorable results [32–34], with vascular endothelial growth factor showing the greatest effect in the clinical setting [35–37]. Comparable improvement in vascularity has also been shown in animal studies [38, 39], by augmenting the production of these factors through gene therapy. Using this approach, several clinical trials have been undertaken to investigate their effects on neovascularization in ischemic heart disease [40, 41] and peripheral vascular diseases [42].
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Other Potential Effects of Bone-Marrow–Derived Cells
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As the debate on whether bone-marrow–derived cells can transdifferentiate into cardiomyocytes or vascular tissue continues, there is increasing evidence suggesting that they have an indirect supportive role in myocardial repair. Apart from promoting neovascularization indirectly through its secretion of angiogenic factors as previously discussed, bone-marrow–derived cells also secrete other cytokines and growth factors (see below) that may influence the loss of cardiomyocytes in response to injury and the regeneration of cardiac tissue by native heart cells.
Bone Marrow as a Source of Cytokines
In addition to angiopoietin-1, vascular endothelial growth factor, hepatocyte growth factor, and fibroblast growth factor, several studies [29, 30, 43] have shown that bone-marrow–derived cells are capable of secreting an array of cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor 
, transforming growth factor-ß, monocyte chemoattractant protein, placental growth factor, stem cell derived factor-1, metalloproteinases, plasminogen activator, granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF). It is recognized that some of the cytokines such as IL-1, IL-6, tumor necrosis factor-, and transforming growth factor-ß play a pivotal role in tissue responses to injury and are upregulated in the bone-marrow–derived cells during hypoxic injury [30]. Other cytokines such as GM-CSF and G-CSF are believed to orchestrate the recruitment, mobilization, and homing of different bone-marrow–derived stem cells during tissue repair [44]. This ability of G-CSF has been used in animal and clinical studies as a means to increase the number of circulating bone-marrow–derived stem cells, although they may influence other tissue regeneration processes [45–47]. As with most cytokines, their effects may depend on the microenvironment of the target tissue, and on the interactions with other cells and cytokines. A detailed discussion of their effects is beyond the scope of this review; however, it can be inferred from the existing literature that bone-marrow–derived cells play a part in modulating tissue response to injury through various mechanisms that may influence the degree of cardiomyocyte loss and native cell regeneration in the heart.
Reduction in Cardiomyocyte Loss
The administration of multipotent adult progenitor cells and endothelial progenitor cells has been associated with reduced apoptosis after myocardial injury in animal models [10, 25]. The mechanism of this effect is unclear; but it has been shown that improved neovascularization may provide the critical perfusion to the viable myocytes around the peri-infarct areas, which would have otherwise undergone apoptosis [25, 26]. Our laboratory has recently demonstrated that bone-marrow–derived cells are able to directly reduce necrosis and apoptosis of the human myocardium in an in vitro model of simulated ischemia through the PKC and p38 MAPK pathways [48]. Therefore, it is possible that the bone-marrow–derived cells may contribute to a reduction in cardiomyocyte loss by direct and indirect mechanisms. Clearly, this is an important area that warrants further investigations.
Stimulation of Proliferation of Native Heart Cells?
The potential existence of native cardiac progenitors is one of the most topical issues in cardiovascular science in recent years, as it opens the door for new therapeutic opportunities for heart disease. So far, the identified putative cardiac stem cells are small round cells, with a high nuclear to cytoplasm ratio, and express c-kit and Sca-1 protein [49]. These cells are clonogenic, self-renewing, pluripotential, and are grouped in niches especially in the atria and the apex of the heart. Although in culture conditions, these cells do not develop full cardiomyocyte phenotype, they can develop a mature cardiac phenotype when transplanted into the border zone of the infarcted heart, and regenerate the entire myocardium [49]. It remains uncertain whether these cells share any similarities to another population of heart-derived Sca-1 cells that do not express cardiac, endothelial, or hematopoietic markers [50], but exhibit similar capabilities.
More recently, another group of putative cardiac progenitors that express islet 1 (lsl 1), a LIM domain transcription factor found predominantly in embryonic and fetal development [51], has been described. Most of these cells are found in the outflow tract, right heart, and left atrium during early development. However, as cells differentiate, lsl 1 is switched off, and they become virtually undetectable in adulthood, making it difficult to establish their physiologic significance in the adult heart.
It is possible that the transplantation of bone-marrow–derived cells into the heart can stimulate the development of these putative cardiac progenitors. So far, there is no information on this potential mechanism. However, it can be speculated that the growth factors and cytokines produced by bone-marrow–derived cells may play a part in such an effect. Indeed, the elucidation of this potential mechanism also requires more investigations to reap its full potential in clinical practice.
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Clinical Trials on Bone Marrow Transplantation to Repair the Damaged Heart
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After early encouraging experimental results, there was great enthusiasm to apply cell transplantation to repair the damaged heart in clinical settings, even before the underlying mechanisms were understood. One of the first reports of such application in cardiac disease utilized skeletal myoblast transplantation in patients with poor ventricular function receiving concurrent coronary artery revascularization [52, 53]. Even though there was improvement in ventricular function in those cell transplant recipients, a few patients experienced severe ventricular arrhythmias requiring the insertion of implantable defibrillators [53]. Subsequently, experimental studies observed failure of electromechanical coupling of the skeletal myoblasts with resident cardiomyocytes [54], which may account for the fatal ventricular arrhythmias. By contrast, the safety and feasibility of transplantation of autologous bone-marrow–derived cells for the treatment of poor cardiac function in myocardial disease was rapidly demonstrated in several phase 1 trials [55–58].
There are a number of key questions that need to be addressed by clinical trials. First and uppermost, can bone-marrow–derived cells improve myocardial function in the failing heart? If so, which groups of patients will benefit from it? What is the optimal time for cell transplantation after an acute myocardial infarction? What is the optimal number of cells required to attain maximum benefit? Which is the best route of administration? How many times should the cells be administered? Should cell transplantation be carried out concurrently with coronary revascularization? So far, most of the published trials have been nonrandomized, and therefore the results have to be interpreted with caution. The current clinical trials also differ significantly in methodology, which make comparisons between trials difficult.
Bone Marrow Transplantation After Acute Myocardial Infarction
The BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial was one of the first randomized control trials to investigate the effects of intracoronary autologous bone-marrow–derived cells delivery within a week after percutaneous coronary intervention for acute myocardial infarction [59] (Table 2). Sixty patients were randomly assigned to become controls or to be treated with autologous bone-marrow–derived cells through coronary artery delivery within a week of their successful percutaneous coronary intervention. The primary endpoint was the change in the patient's left ventricular ejection fraction between the baseline and 6-month follow-up cardiac magnetic resonance imaging scan. After this period, a significant increase in the mean global left ventricular ejection fraction was observed in the patient receiving bone marrow cells as compared with controls. There was also enhancement of the systolic function in myocardial segments adjacent to the infarcted areas in the group treated with bone marrow cells, supporting the findings of most earlier case-control studies [57, 60]. A subsequent randomized study on bone-marrow–derived cell therapy in patients with acute myocardial infarction has also corroborated these results [61]. Although the infarct size and left ventricular end diastolic volume remained unchanged in the BOOST trial, some studies have demonstrated reduced infarct size in patients treated with bone marrow cells [57, 61]. Only two studies to date did not observe any significant hemodynamic improvement—a small observational study on 5 patients [62], and the ASTAMI randomized control trial [63, 64]. In the preliminary results of the ASTAMI study, no significant improvement in left ventricular ejection fraction was observed, even though earlier nonrandomized control trials suggested that it was possible to have regional wall motion improvement in the absence of significant change in the global left ventricular ejection fraction. These discrepancies in the reported results could be partially due to variations in the trial protocols, such as the methods of assessing myocardial function, study endpoints, patient selection criteria, and bone-marrow–derived cell preparation. To establish the true benefits of bone-marrow–derived cell transplantation in acute myocardial infarction, more randomized studies will be necessary using a "common" methodology to facilitate better comparative analysis.
Bone Marrow Transplantation in Chronic Ischemic Cardiac Disease
In patients with chronic ischemic cardiac disease, a small randomized control study and several preliminary nonrandomized studies have studied the effects of bone marrow cells administered to viable ischemic myocardium, and have reported various degree of functional improvements [56, 65–68] (Table 3). For nonviable myocardial areas, one of the earliest phase I studies performed by our group has showed that when autologous bone-marrow–derived cells were administered through transepicardial intramuscular injections, significant improvement in regional wall motion was observed only in those injected areas that were simultaneously revascularized [58, 69]. This suggests that in the nonviable myocardium, restoration of normal myocardial perfusion is essential to obtain the beneficial effects of bone-marrow–derived cells. The findings are supported by the preliminary results of an ongoing randomized control trial, in which the efficacy of the intramyocardial versus intracoronary administration of bone marrow cells is also investigated [70].
Routes of Administration
In the ideal scenario, the administration of the bone-marrow–derived cells should be simple, as minimally invasive as possible, and permit the delivery of the optimal numbers of cells needed to obtain maximal clinical benefits. Different routes of administration are possible: transvenous, intracoronary, or intramuscular (either through transepicardial or transendocardial injections). Although transvenous administration of bone-marrow–derived cells is the simplest and least invasive method, a magnetic resonance imaging study using tagged bone-marrow–derived cells [71] has shown a significantly lower retention of the cells on the heart by this method than with intracoronary administration, which is the most common method used in trials of patients with acute myocardial infarction. As mentioned above, whether intracoronary administration of bone-marrow–derived cells is comparable or superior to intramuscular delivery through the transepicardial route is under investigation in a randomized control trial by our group [70]. Theoretically, intramuscular injection of bone-marrow–derived cells can accurately deliver a higher local concentration of cells to the area requiring treatment under direct vision. However, its main disadvantage is that it is more invasive, and because of this, it has been usually performed in conjunction with open-heart surgery. Recently, the application of electromechanical mapping to guide transendocardial injection [65, 72] has provided a potentially less invasive way to deliver the cells intramuscularly.
In an attempt to limit the invasiveness of cellular therapy, cytokines like G-CSF have been used to mobilize bone-marrow–derived cells for myocardial repair after a myocardial infarction [46, 73]. Initial results have shown improvement in cardiac function and perfusion in patients receiving revascularization and G-CSF therapy early after a myocardial infarction. However, it is uncertain if this improvement was due to the mobilized stem cells or to the direct effect of cytokines on injured myocardium. There were nevertheless concerns about its safety owing to the observations of early restenosis of stented coronary vessels in some of the patients after G-CSF administration [46].
The Ideal Cell Type
Bone-marrow–derived cells are usually harvested from the iliac crest, and the bone marrow mononuclear layer cells are separated using a density gradient for transplantation in most studies. These cells are a composite mixture of different stem cell subtypes including hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, and multipotent adult progenitor cells, all of which have the potential to improve myocardial function. While some studies had attempted to expand these cells by culturing them for a period before their administration [57, 61], others had tried to isolate a subgroup of cells to promote a specific role, like the isolation of CD133+ cells to promote angiogenesis [55]. However, until a more accurate classification and isolation system is devised, it may not be possible to isolate pure population of the various subtypes of stem cells. These technical constraints make the precise evaluation of their individual contribution in myocardial regeneration difficult, and therefore the selection of the optimal cell type for transplantation.
Based on the results of present clinical trials, the use of bone marrow transplantation in both acute myocardial infarction and in chronic ischemic heart failure appears safe and beneficial in most of the studies. However, this benefit needs to be confirmed by larger randomized control trials. The best route of administration and the optimal cell type also need to be determined by more detailed studies, in addition to a better understanding of the underlying mechanism of action.
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Comment
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The transplantation of autologous bone-marrow–derived cells represents an attractive, promising approach in the treatment of heart failure, as these cells have been reported to exhibit the potential to repair the damaged heart both directly and indirectly in experimental studies. They are also relatively easy to prepare and administer in the clinical setting, while avoiding the need of long-term immunosuppressive therapy. Hence, several clinical trials on their applications in different cardiac disorders have been initiated before the precise scientific basis of their beneficial effects is fully appreciated. Despite encouraging results from some of these trials, several hurdles lie ahead. A better understanding of the repairing mechanisms of bone-marrow–derived cells together with advances in the identification and isolation of the various cell subpopulations will be necessary for the establishment and refinement of this treatment modality. Improvements in the ability to track the fate of the transplanted cells will also facilitate this process. For this endeavor, sufficient resources should be allocated to elucidate the ideal cell type to use and to identify the best isolation techniques and route of administration. The possibility of using cell transplantation in conjunction with other novel techniques such as gene therapy or cytokine administration should also be defined to fully optimize its therapeutic potential. These tasks will require a close cooperation between cell biologists and clinicians, so that the use of cell therapy in the treatment of cardiac diseases may become a reality in the future.
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Acknowledgments
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We wish to acknowledge the British Heart Foundation (Grant PG04050) and Bristol-Myers Squibb for their respective research fellowships. We are also grateful for Nicola Harris's secretarial assistance.
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Abstract
Introduction
