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.     

Myoblast cell sheet transplantation enhances the endogenous regenerative abilities of infant hearts in rats with myocardial infarction

The shortage of heart transplantation donors for infants is severe. Regenerative cell therapy has been expected to offer new methods of treatment, and this study was about regenerative cell therapy for infant hearts. The aims of the present study were to clarify the effects of regenerative cell therapy on the infant heart. The heart impairment model and tissue‐engineered myoblast cell sheets were used for regenerative cell therapy. Infant rats (n = 54) aged 2 weeks and adult rats aged 12 weeks (n = 35) were used. Myocardial infarction (MI) was induced as the heart impairment model and triple‐layer myoblast cell sheets were used for transplantation to MI lesions. Infant rats after MI had better self‐regenerative ability in wall thickness, fibrosis and cardiac function and we observed greater numbers of proliferating cardiomyocytes than in adults. Moreover, infant MI rats treated with myoblast cell sheets showed better results in wall thickness, fibrosis and cardiac function than infant MI rats without myoblast cell sheets, because of the positive effect that myoblast cell sheets had on proliferating cardiomyocytes, increasing vascular networks and accumulating c‐kit‐positive cells. We clarified that regenerative cell therapy enhances the endogenous regenerative ability of infant hearts in rats with MI; moreover, it has a greater therapeutic effect on infant hearts than on adult hearts, because of the ability of infant hearts for cardiomyocyte proliferation. The present paper provides essential new data for clinical therapy in infant patients. Copyright © 2015 John Wiley & Sons, Ltd.     

SDF-1 in myocardial repair

Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results.     

Combining stem cells in myocardial infarction: The road to superior repair?

Myocardial infarction irreversibly destroys millions of cardiomyocytes in the ventricle, making it the leading cause of heart failure worldwide. Over the past two decades, many progenitor and stem cell types were proposed as the ideal candidate to regenerate the heart after injury. The potential of stem cell therapy has been investigated thoroughly in animal and human studies, aiming at cardiac repair by true tissue replacement, by immune modulation, or by the secretion of paracrine factors that stimulate endogenous repair processes. Despite some successful results in animal models, the outcome from clinical trials remains overall disappointing, largely due to the limited stem cell survival and retention after transplantation. Extensive interest was developed regarding the combinational use of stem cells and various priming strategies to improve the efficacy of regenerative cell therapy. In this review, we provide a critical discussion of the different stem cell types investigated in preclinical and clinical studies in the field of cardiac repair. Moreover, we give an update on the potential of stem cell combinations as well as preconditioning and explore the future promises of these novel regenerative strategies.     

Myocyte renewal

In contrast to conventional assumption that myocytes are never renewed after birth, a growing body of evidence suggests that human cardiac myocytes might divide in myocardial infarction and severe heart failure. Bone marrow cells may also contribute to myocyte regeneration, when injected or mobilized into systemic circulation by cytokines. A clinical study demonstrated that intracoronary administration of autologous bone marrow significantly improved the cardiac function after acute myocardial infarction. No adverse effect was found. Cell therapy using adult stem cells is anticipated to be an effective treatment of heart failure.     

A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates

Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1⁺ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1^– cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1⁺ cells did not. We therefore believe that the SSEA-1⁺ progenitors that we have described here have the potential to be used in cardiac regenerative medicine.     

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’.     

High-resolution X-ray microtomography for three-dimensional imaging of cardiac progenitor cell homing in infarcted rat hearts

The recent introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathological heart and has opened a search for new therapeutic strategies. Recent published reports have contributed to identifying possible cellular therapy approaches to generate new myocardium, involving transcoronary and intramyocardial injection of progenitor cells. However, one of the limiting factors in the overall interpretation of clinical results obtained by cell therapy is represented by the lack of three-dimensional (3D) high-resolution methods for the visualization of the injected cells and their fate within the myocardium. This work shows that X-ray computed microtomography may offer the unique possibility of detecting, with high definition and resolution and in ex vivo conditions, the 3D spatial distribution of rat cardiac progenitor cells, labelled with iron oxide nanoparticles, inside the infarcted rat heart early after injection. The obtained 3D images represent a very innovative progress as compared to experimental two-dimensional (2D) histological analysis, which requires time-consuming energies for image reconstruction in order to provide the overall distribution of rat clonogenic cells within the heart. Through microtomography, we were able to observe in 3D the presence of these cells within damaged cardiac tissue, with important structural details that are difficult to visualize by conventional bidimensional imaging techniques. This new 3D-imaging approach appears to be an important way to investigate the cellular events involved in cardiac regeneration and represents a promising tool for future clinical applications.     

New cell therapies in cardiology

Even today, cardiovascular disease remains the leading cause of death globally. Cardiological conditions such as myocardial infarction, ischemic injury and chronic cardiomyopathy result in permanent cardiac tissue damage followed by heart failure. Current therapies primarily aim to trigger the pathological remodeling that occurs after cardiac injury and also to reduce risk factors involved in cardiovascular diseases. Animal model studies over the last decade indicate that the systematic administration of autologous and allogeneic stem cells possesses therapeutic potential to improve overall cardiac functions. This evidence robustly indicates that cardiac tissue has the potential to undergo a systematic repair process. The past few years have also witnessed a splurge in clinical research that particularly aims to explore the regenerative properties of the naive stem cells to restore cardiac functions. The mechanisms involved in stem cell therapy remain unclear. The magnitude of benefit demonstrated in animal models is yet to be completely translated into humans. The future of cardiac research will require tangible synchrony between clinicians and basic scientists to unravel the precise mechanism of stem cell therapy. It is also pivotal to define an ideal cell type and a suitable cell delivery technique that provide maximum benefit, while eliminating the grey areas in translational cardiology research. In this article, the authors review the properties and therapeutic potential of the stem cell plethora reported for cardiac repair and regeneration, recent stem cell therapies, mode of action, their delivery techniques, recent clinical developments and the future for these stem cell therapies in cardiology.     

Gene therapy for myocardial regeneration

Most of cardiac myocytes have lost their ability to proliferate and differentiate into new myocytes. Therefore, myocyte regeneration and replacement in adult myocardium was thought to be impossible by medical community. However, recent findings in cardiovascular researches provide the possibility that gene therapy and stem cell therapy could have supportive effects on myocyte regeneration and myocardial revascularization in damaged heart. Here, we presented recent progress, especially, in gene therapy for myocardial regeneration under ischemic heart disease and heart failure.     

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.     

Mesenchymal stem cells for cardiac cell therapy

Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy.     

Thymosin β4: multiple functions in protection,repair and regeneration of the mammalian heart

Introduction: Despite recent improvements in interventional medicine, cardiovascular disease still represents the major cause of morbidity worldwide, with myocardial infarction being the most common cardiac injury. This has sustained the development of several regenerative strategies based on the use of stem cells and tissue engineering approaches in order to achieve cardiac repair and regeneration by enhancing coronary neovascularization, modulating acute inflammation and supporting myocardial regeneration to provide new functional muscle.

Areas covered: The actin monomer binding peptide, Thymosin β4 (Tβ4), has recently been described as a powerful regenerative agent with angiogenic, anti-inflammatory and cardioprotective effects on the heart and which specifically acts on its resident cardiac progenitor cells. In this review we will discuss the state of the art regarding the many roles of Tβ4 in preserving and regenerating the mammalian heart, with specific attention to its ability to activate the quiescent adult epicardium and specific subsets of epicardial progenitor cells for repair.

Expert opinion: The therapeutic potential of Tβ4 for the treatment of cardiac failure is herein evaluated alongside existing, emerging and prospective novel treatments.     

Surgical options for the treatment of heart failure

This article will examine the role of specific surgical interventions for congestive heart failure (CHF). The most definitive surgical option for severe end-stage heart failure is cardiac transplantation. In general, patients considered for heart transplant should have severe heart disease despite all other therapies with a high risk of death within 1 year. Noncardiac conditions that would by themselves shorten life expectancy or increase the risks of rejection, infection, or other fatal complication, should not be present. However, in light of the limited donor pool, complications associated with long-term immunosuppressive therapy, and the ever-increasing number of CHF patients, the role of cardiac transplantation for CHF will continue to be limited. The conduct of and evaluation for cardiac transplantation has been well described previously and therefore will not be evaluated in this review (1); however, there has been recent progress in the genetic modification of animal organs for potential use in transplantation (xenografts) (2). If these developments come to fruition, then cardiac transplantation/organ replacement may become a surgical option for a much greater number of CHF patients. One alternative approach to complete cardiac transplantation is the surgical placement of transformed cells into the diseased myocardium, briefly discussed under "Future Directions." This article will examine surgical options that are currently being used for CHF patients, surgical modalities that are currently under clinical evaluation, and finally, potential future therapies with respect to surgical options for heart failure.     

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.     

A Canadian perception of the nursing practice, research, and theoretical implications associated with autologous cell transplantation

Heart failure is a progressive disorder. An estimated 400,000 Canadians are diagnosed annually with heart failure, and a quarter experience severe heart failure that is unresponsive to medical therapy. Autologous cell transplantation has been proposed as a new approach for cardiac repair and holds enormous potential for the regeneration of injured myocardium cells. Currently, autologous cell transplantation is under investigation in Canada. Its use as a treatment alternative for heart failure patients has been established over the past 5 years across Europe and the United States. This article will present a Canadian perception of the nursing practice, research, and theoretical implications associated with this new and innovative therapy.     

白血病干/祖细胞及靶向治疗研究进展

人类白血病是一种由造血干/祖细胞或祖细胞染色体变异或者渐进性改变的恶性克隆性疾病,耐药与复发是白血病治疗失败的两大主要原因。近年来对于白血病患者体白血病干/祖细胞（LSPC）的发现和研究,深入阐述了白血病的发生机制,并探索了针对LSPC的靶向治疗。本文简要介绍LSPC的分子生物学特性以及LSPC靶向治疗,诸如针对LSPC表面分子的靶向治疗,针对特殊分子调控机制的靶向治疗,针对干扰LSPC与骨髓微环境间相互作用的靶向治疗等的研究进展。     

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.     

Challenges towards regenerative medicine

Regenerative medicine is a promising approach to treat patients with severe cardiac failure. Since embryonic stem cells (ES cells) easily differentiate into cardiomyocytes, ES cells are thought to be a good candidate resource for cardiac cell transplantation therapy. However, molecular mechanism of cardiac differentiation is still largely unknown. Here we discuss our present approach to understand the mechanism of cardiogenesis at the molecular level as well as novel genes and cascades that are important for cardiac differentiation. Further observation will help to establish the new strategy of regenerative medicine for patients with cardiac failure.