Stem cell therapy after myocardial infarction: ready for clinical application?

The discovery of stem cells capable of generating angiogenic or contractile cells and structures might offer new treatment options for patients suffering from heart disease. In particular, embryonic stem cells are considered to have great potential for regenerative medicine and tissue engineering. Studies suggest that delivery or mobilization of stem and progenitor cells might improve tissue perfusion and contractile performance of the damaged heart; however, the underlying mechanisms are poorly understood. Fusion or trans-differentiation into cardiomyocytes or vascular cells are considered rare events of cellular engraftment, and adult stem cells are now considered as 'regenerator cells', acting via paracrine effects of cytokines, or by activation of resident stent cells, thereby supporting the myocardial healing mechanisms after injury. Administration of autologous hematopoietic stem cells or mobilization of endogenous stem cells has been shown to be safe after myocardial infarction or cardiomyopathies, whereas skeletal myoblasts are considered to be hazardous due to the occurrence of life-threatening arrhythmias. This review focuses on the use of adult human stem cells for treating myocardial infarction and cardiomyopathy, and discusses recent preliminary efficacy data, which suggest that 'regenerator cells' might have the potential to improve myocardial perfusion and contractile performance in patients suffering from myocardial infarction, severe ischemic heart disease and chronic heart failure.     

Isolation and expansion of resident cardiac progenitor cells

After myocardial infarction, loss of viable cardiomyocytes severely impairs cardiac function. Recently, stem cell transplantation has been put forward as a promising approach to repair the damaged heart. Although several clinical trials have already been performed, the dominant beneficial effects are probably due to neoangiogenesis and arteriogenesis. However, replacement of cardiomyocytes is vital to improve cardiac function in the long term. Stem cells and progenitor cells, with the capacity to differentiate into cardiomyocytes, have been described in both embryonic and adult tissues. Upon stimulation, cardiac progenitor cells proliferate and differentiate into cardiomyocytes, vascular smooth muscle cells, and endothelial cells. Currently however, high proliferation rates and differentiation of cardiac progenitor cells beyond the fetal stage have not yet been achieved. Full differentiation into adult cardiomyocytes in vitro and in vivo might be important for efficient integration with the host environment and therefore more research is needed to study factors that influence proliferation and differentiation. Here we will discuss the isolation of cardiac progenitor cells, their potential to differentiate into various cell types needed for cardiac repair, the possible mechanisms behind these events, and how these cells may be implemented in future clinical settings.     

The stuttering progress of cell therapy for heart disease

Stem cell therapy has emerged as a potential therapeutic strategy for myocardial infarction (MI). Multiple cell types used to regenerate the injured heart have been tested in clinical trials. The results of studies of skeletal myoblasts (SKMs) have been resoundingly negative, and the bone marrow-derived-cell experience leaves much to be desired. A number of lessons arise from the large-scale bone marrow-derived-cell trials: (i) efficacy has been inconsistent and, overall, modest; however, unexpectedly meaningful benefits on clinical end points have been reported; (ii) cardiac engraftment of cells is disappointingly low, and delivery methods need to be optimized and combined with strategies to boost retention; (iii) the cardiomyogenic potential of bone marrow cells is low; however, functional benefit can be achieved through indirect pathways; and (iv) autologous cell therapy has severe limitations; highly standardized allogeneic cell products are attractive. Given the spotty trajectory of cell therapy to date, a more systematic approach to product development and preclinical optimization will facilitate more effective clinical translation.     

Cell‐based therapies for cardiac disease: a cellular therapist's perspective

Cell‐based therapy is an exciting, promising, and a developing new treatment for cardiac diseases. Stem cell–based therapies have the potential to fundamentally transform the treatment of ischemic cardiac injury and heart failure by achieving what would have been unthinkable only a few years ago—the Holy Grail of myocardial regeneration. Recent therapeutic approaches involve bone marrow (BM)‐derived mononuclear cells and their subsets such as mesenchymal stem/stromal cells (MSCs), endothelial progenitor cells as well as adipose tissue–derived MSCs, cardiac tissue–derived stem cells, and cell combinations. Clinical trials employing these cells have demonstrated that cellular therapy is feasible and safe. Regarding delivery methods, the safety of catheter‐based, transendocardial and ‐epicardial stem cell injection has been established. However, the results, while variable, suggest rather modest clinical efficacy overall in both heart failure and ischemic heart disease, such as in acute myocardial infarction. Future studies will focus on determining the most efficacious cell type(s) and/or cell combinations and the most reasonable indications and optimal timing of transplantation, as well as the mechanisms underlying their therapeutic effects. We will review and summarize the clinical trial results to date. In addition, we discuss challenges and operational issues in cell processing for cardiac applications.     

The proarrhythmic risk of cell therapy for cardiovascular diseases

Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell-cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation.     

The proarrhythmic risk of cell therapy for cardiovascular diseases

Stem cell therapy is an emerging therapeutic approach for the treatment of cardiovascular diseases. Experimental studies have demonstrated that different types of stem cells, including bone marrow-derived cells, mesenchymal stem cells, skeletal myoblasts, and cardiac progenitor cells and embryonic stem cells, can improve cardiac function after myocardial injuries. Nevertheless, the potential proarrhythmic risk after stem cell transplantation remains a major concern. Several mechanisms, including the immaturity of electrical phenotypes of the transplanted cardiomyocytes, poor cell–cell coupling and cardiac nerve sprouting, may contribute to arrhythmogenic risk after stem cell transplantation. This review summarizes the potential theoretical arrhythmogenic mechanisms associated with different types of stem cells for the treatment of cardiovascular diseases. Nevertheless, current experimental and clinical data on the proarrhythmic risk for different types of stem cell transplantation are limited, and await further experimental and clinical investigation.     

What You See is What You Get? Imaging of Cell Therapy for Cardiac Regeneration

An estimated 7.3 million people die from coronary heart disease each year, according to the recent report of the World Health Organization. In the hope of true regeneration of the infarcted or failing heart, stem and progenitor cells from various sources have gained massive attention in recent years. Data from animal and human studies have been conflicting, and cell type and application varied significantly across all protocols. It now has become clear that many details of cardiac cell therapy remain to be elucidated. In this context comprehensive in vivo imaging methods are essential tools to evaluate mechanisms of cell engraftment and function. In the present review we summarize current imaging modalities for tracking transplanted cells in animals and humans including most recent developments in the field.     

From cardiac repair to cardiac regeneration – ready to translate?

Cardiovascular disease is a major public health challenge in the western world. Mortality of acute events has improved, but more patients develop HF – a condition affecting up to 22 million people worldwide. Cell transplantation is the first therapy to attempt replacement of lost cardiomyocytes and vasculature to restore lost contractile function. Since the first reported functional repair after injection of autologous skeletal myoblasts into the injured heart in 1998, a variety of cell types have been proposed for transplantation in different stages of cardiovascular disease. Fifteen years of preclinical research and the rapid move into clinical studies have left us with promising results and a better understanding of cells as a potential clinical tool. Cell-based cardiac repair has been the first step, but cardiac regeneration remains the more ambitious goal. Promising new cell types and the rapidly evolving concept of adult stem and progenitor cell fate may enable us to move towards regenerating viable and functional myocardium. Meeting a multidisciplinary consensus will be required to translate these findings into safe and applicable clinical tools.     

Comparison of adult versus embryonic stem cell therapy for cardiovascular disease: Insights from molecular imaging studies

In the previous decade, cardiac cell replacement therapy has emphasized adult stem cells such as skeletal myoblasts, bone marrow mononuclear cells, and endothelial progenitor cells. Functional restoration of systolic function has been documented in most of these cases, but beneficial results have rarely persisted for significant lengths of time due to failure of cells to survive and the as yet controversial role of transdifferentiation into endogenous tissue. Future efforts at cell replacement therapy will likely focus upon cellular derivatives of embryonic stem (ES) cells, which can be induced to form any cell type of the body. Use of ES cells, however, presents several novel considerations such as teratoma formation and immune rejection. This review summarizes the current progress made in the field of cardiac cell replacement therapy and the role noninvasive imaging can play in realizing the therapeutic potential of stem cells.     

From cardiac repair to cardiac regeneration--ready to translate?

Cardiovascular disease is a major public health challenge in the western world. Mortality of acute events has improved, but more patients develop HF--a condition affecting up to 22 million people worldwide. Cell transplantation is the first therapy to attempt replacement of lost cardiomyocytes and vasculature to restore lost contractile function. Since the first reported functional repair after injection of autologous skeletal myoblasts into the injured heart in 1998, a variety of cell types have been proposed for transplantation in different stages of cardiovascular disease. Fifteen years of preclinical research and the rapid move into clinical studies have left us with promising results and a better understanding of cells as a potential clinical tool. Cell-based cardiac repair has been the first step, but cardiac regeneration remains the more ambitious goal. Promising new cell types and the rapidly evolving concept of adult stem and progenitor cell fate may enable us to move towards regenerating viable and functional myocardium. Meeting a multidisciplinary consensus will be required to translate these findings into safe and applicable clinical tools.     

Microvascular angina. Cardiovascular investigations regarding pathophysiology and management

A significant minority of patients with chest pain who undergo cardiac catheterization are found to have angiographically normal coronary arteries. Over the past 25 years, several studies have shown that a subset have demonstrable abnormalities in coronary flow and cardiac function; however, only a minority of these patients have convincing evidence for myocardial ischemia during stress, and alternative mechanisms have been explored to explain the frequent and debilitating symptoms of pain experienced by the majority of these patients undergoing study. Abnormal visceral nociception appears to be a fundamental abnormality in this population, whether or not demonstrable abnormalities in coronary flow or cardiac function can be demonstrated.     

Skeletal myoblast transplantation for cardiac repair

Cell transplantation is gaining interest as a potentially new means of improving function of the failing heart through replacement of lost cardiomyocytes with new contractile cells. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also being considered, particularly bone marrow stem cells which are credited for a plasticity that might allow them to change their phenotype in response to environmental cues. Several key issues still need to be addressed including: the comparative efficacy of different donor cell lineages in relation to the patient's clinical condition (i.e., ischemia vs. heart failure, the mechanism by which cell engraftment improves cardiac function, the enhancement of cell survival and functional integration within the recipient tissue, and the development of minimally invasive cell delivery techniques. In parallel to these laboratory studies, clinical trials are now being implemented to generate efficacy data. Altogether, these efforts should allow the assessment of whether and to what extent cell transplantation may ameliorate function of the failing heart.     

Skeletal myoblast transplantation for cardiac repair

Cell transplantation is gaining interest as a potentially new means of improving function of the failing heart through replacement of lost cardiomyocytes with new contractile cells. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also being considered, particularly bone marrow stem cells which are credited for a plasticity that might allow them to change their phenotype in response to environmental cues. Several key issues still need to be addressed including: the comparative efficacy of different donor cell lineages in relation to the patient’s clinical condition (i.e., ischemia vs. heart failure, the mechanism by which cell engraftment improves cardiac function, the enhancement of cell survival and functional integration within the recipient tissue, and the development of minimally invasive cell delivery techniques. In parallel to these laboratory studies, clinical trials are now being implemented to generate efficacy data. Altogether, these efforts should allow the assessment of whether and to what extent cell transplantation may ameliorate function of the failing heart.     

Cellular cardiac regenerative therapy in which patients?

Cell-based myocardial regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles owing to ischemic and nonischemic myocardial diseases. A variety of myogenic and angiogenic cell types have been proposed, such as skeletal myoblasts, mononuclear and mesenchymal bone marrow cells, circulating blood-derived progenitors, adipose-derived stromal cells, induced pluripotent stem cells, umbilical cord cells, endometrial mesenchymal stem cells, adult testis pluripotent stem cells and embryonic cells. Current indications for stem cell therapy concern patients who have had a left- or right-ventricular infarction or idiopathic dilated cardiomyopathies. Other indications and potential applications include patients with diabetic cardiomyopathy, Chagas heart disease (American trypanosomiasis), ischemic mitral regurgitation, left ventricular noncompacted myocardium and pediatric cardiomyopathy. Suitable sources of cells for cardiac implant will depend on the types of diseases to be treated. For acute myocardial infarction, a cell that reduces myocardial necrosis and augments vascular blood flow will be desirable. For heart failure, cells that replace or promote myogenesis, reverse apoptopic mechanisms and reactivate dormant cell processes will be useful. It is important to note that stem cells are not an alternative to heart transplantation; selected patients should be in an early stage of heart failure as the goal of this regenerative approach is to avoid or delay organ transplantation. Since the cell niche provides crucial support needed for stem cell maintenance, the most interesting and realistic perspectives include the association of intramyocardial cell transplantation with tissue-engineered scaffolds and multisite cardiac pacing in order to transform a passive regenerative approach into a ‘dynamic cellular support’, a promising method for the creation of ‘bioartificial myocardium’.     

Adult stem cell therapy for heart failure

Evidence indicates that bone marrow and many other somatic tissues contain pluripotent or multipotent adult stem cells as well as progenitor cells which can differentiate into cells of various phenotypes. Experimental studies strongly suggest that the normal function of the marrow derived adult stem cells is for tissue repair, and that they can be recruited by signals originating from injured tissue, traffic through the circulation and home into the injured site to undergo milieu dependent differentiation in situ. In the heart, these cells may differentiate into cardiomyocytes, vascular cells and scar tissue, thus participating in vasculogenesis, scar maturation and modulation of the remodelling process of the myocardium. To augment such a healing process, cell therapy using such cells, which may be preprogrammed if desired, may have donor cells implanted by direct injection, coronary infusion and, in some cases, by systemic intravenous administration. Improved ventricular function has been reported in myocardial infarct animal models. Although early Phase I clinical trials have been initiated for both autologous myoblast and autologous marrow cell transplants with favourable reported outcomes, the data are still too preliminary to draw definitive conclusions regarding their safety and efficacy. Additional mechanistic and translational preclinical investigations are essential, and well designed clinical studies are required before the great potential of adult stem cell therapy can be fully realised and benefit the vast number of heart failure patients.     

Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1–positive (Sca-1–positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.     

The epicardium in cardiac repair: from the stem cell view

During heart development, the epicardium provides cardiogenic progenitor cells and, together with the myocardium, directs lineage specification and coordinates both myocardial growth and coronary vasculature formation. In the adult heart, the established function of the epicardium is to provide a smooth surface that, together with the pericardium, favors heart movement during contraction and relaxation. Recently, epicardial precursor cells with the ability to differentiate into cardiomyocytes and vascular cells have been identified and the quiescent nature of the adult epicardium has been questioned. Interestingly, the signaling pathways involved in this process appear to be regulated, in the adult heart, by mechanisms similar to those in the embryonic heart. This review will summarize the properties of the embryonic epicardium and will focus on recent advances on the role of the adult epicardium in cardiac regeneration. Specifically, we will present aspects of epicardial cell biology that may be relevant to the development of new therapeutic approaches aimed at inducing heart repair following injury.     

Cardiospheres and cardiosphere-derived cells as therapeutic agents following myocardial infarction

Heart disease is a major cause of morbidity and mortality. Cellular therapies hold significant promise for patients with heart disease. Heart-derived progenitor cells are capable of repairing a diseased heart through modulation of growth factor milieu and temporary engraftment leading to endogenous repair. The proof-of-concept CADUCEUS clinical trial using cardiosphere-derived cells has shown evidence of therapeutic cardiac tissue regeneration. Future clinical trials are now being planned to generate additional safety and efficacy data in the hopes of building toward an approved cellular therapy for heart disease.     

Therapeutic potential of adult progenitor cells in cardiovascular disease

Cardiovascular diseases are responsible for high morbidity/mortality rates worldwide. Advances in patient care have significantly reduced deaths from acute myocardial infarction. However, the cardiac remodeling processes induced after ischaemia are responsible for a worsening in the heart condition, which in many cases ends up in failure. In the last decade, a novel therapy based on stem cell transplantation is being intensively studied in animal models and some stem cell types (i.e., skeletal myoblasts and bone marrow-derived cells) are already being tested in clinical trials. A novel stem cell population isolated from the bone marrow, termed multipotent adult progenitor cells was characterised a few years ago by its ability to differentiate, at the single cell level, towards cells derived from the three embryonic germ layers. Later on, other pluripotent cell populations have been also derived from the bone marrow. In this overview, the authors outline different stem cell sources that have been tested for their cardiovascular potential and put the regenerative potential of multipotent adult progenitor cells in animal models of acute and chronic myocardial infarction into perspective.     

Therapeutic potential of adult progenitor cells in cardiovascular disease

Cardiovascular diseases are responsible for high morbidity/mortality rates worldwide. Advances in patient care have significantly reduced deaths from acute myocardial infarction. However, the cardiac remodeling processes induced after ischaemia are responsible for a worsening in the heart condition, which in many cases ends up in failure. In the last decade, a novel therapy based on stem cell transplantation is being intensively studied in animal models and some stem cell types (i.e., skeletal myoblasts and bone marrow-derived cells) are already being tested in clinical trials. A novel stem cell population isolated from the bone marrow, termed multipotent adult progenitor cells was characterised a few years ago by its ability to differentiate, at the single cell level, towards cells derived from the three embryonic germ layers. Later on, other pluripotent cell populations have been also derived from the bone marrow. In this overview, the authors outline different stem cell sources that have been tested for their cardiovascular potential and put the regenerative potential of multipotent adult progenitor cells in animal models of acute and chronic myocardial infarction into perspective.