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’.     

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.     

Mesenchymal Stem Cells in Cardiac Repair: Effects on Myocytes,Vasculature, and Fibroblasts

PurposeCardiac pathologies remain a dominant cause of morbidity and mortality within the community. The drive to develop therapies capable of repairing damaged heart tissue to achieve clinically significant restoration of function has motivated the pursuit of novel approaches such as cell therapy. To this end, evidence of therapeutic benefits achieved by using mesenchymal stem cells (MSCs) has captured considerable interest despite a relative lack of information regarding the mechanisms involved. This narrative review synthesizes and interprets the current literature describing mechanisms by which MSCs can elicit cardiac repair, thereby directing attention to avenues of further inquiry.MethodsOVID versions of MEDLINE and EMBASE were searched for studies describing the role of MSCs in mammalian cardiac repair. Additional studies were sourced from the reference lists of relevant articles and other personal files.FindingsMSCs elicit cardiac repair in a range of in vitro systems and animal models of diseases such as myocardial infarction and heart failure. Important mechanisms include the preservation of myocardial contractility, the promotion of angiogenesis, and the modulation of fibrosis. Exposing in vitro MSCs to a microenvironment reflective of that encountered in the injured heart seems to potentiate these therapeutic mechanisms.ImplicationsPromising results in animal studies warrant continuation of clinical MSC cardiac therapy studies. Paracrine functions of MSCs seem to be the dominant mechanism of cardiac repair over direct cellular effects. Although integral, the MSC secretome remains poorly defined. In addition, most of the mechanistic data within the literature have been derived from animal MSC research, necessitating more human MSC-based work.     

Non-contrast-enhanced magnetic resonance angiography: techniques and applications

Research shows that various types of stem cells (SCs) have the ability to rebuild damaged heart tissue. The TIME and Late TIME human trials shed light on the optimum timing of SC therapy administration after myocardial damage. The FOCUS study failed to show a substantial positive effect of bone marrow-derived mononuclear cells in patients suffering from ischemic heart failure; however, some completed human trials do show promise, with improvement in cardiac function. Recent clinical trials have identified a subset of marrow cells that was able to stimulate endogenous adult cardiac SCs where cardiac SCs administration showed promise in the SCIPIO trial. This review addresses some of the lessons learned from clinical trials with SC therapy in ischemic heart failure.     

Modification of mesenchymal stem cells for cardiac regeneration

Importance of the field: Mesenchymal stem cells (MSCs) have the greatest potential for use in cell-based therapy of human heart diseases, especially in myocardial infarcts. The therapeutic potential of MSCs in myocardial repair is based on the ability of MSCs to directly differentiate into cardiac tissue and on the paracrine actions of factors released from MSCs. However, the major obstacle in the clinical application of MSC-based therapy is the poor viability of the transplanted cells due to harsh microenvironments like ischemia, inflammation and/or anoikis in the infarcted myocardium. Recently, various approaches have been implemented in an effort to improve the survival of implanted MSCs through ex vivo manipulation of MSCs.

Areas covered in this review: Major obstacles in MSC-based therapy are discussed, along with recent advances for enhancing therapeutic potential of engrafted MSCs from the past decade.

What the reader will gain: This review focuses primarily on ex vivo manipulation of MSCs before transplantation, which includes pretreatment, preconditioning and genetic modification of MSCs, and future directions.

Take home message: Modification of MSCs before transplantation has developed into a promising option for enhancing the beneficial effects of MSC-based therapy for cardiac repair after myocardial infarction.     

Heal thyself: Potential applicability of stem cell therapy in the management of heart disease

Acute myocardial infarction results in regional necrotic heart tissue that is considered irreversible. Although angioplasty and thrombolytic therapy can remove the offending atherosclerotic plaque and thrombi, both therapies are dependent upon timely recognition and initiation of treatment and thus have a limited window of opportunity. No currently available therapy has the capability to restore cardiomyocytes or to replace myocardial scar tissue with contractile tissue. In animal models, use of a wide range of cells such as fetal cardiomyocytes, skeletal myoblasts, and bone marrow stem cells have been shown to differentiate into functional cardiomyocytes. In addition, transplantation of adult stem cells directly into the area of infarction has shown clinical promise. This article explores the current data on extramedullary hematopoiesis, stem cell differentiation, and stem cell therapy and its ability to repair injured or ischemic cardiac tissue.     

基因修饰干细胞治疗心肌梗死：临床前和临床应用中的相关问题

背景：干细胞具有分化为心肌及血管的潜力,可使缺血部位心肌得以组织修复及血运重建。该特性使干细胞移植成为具有发展前景的治疗缺血性心脏病的新型疗法。但干细胞移植后的长期存活以及远期疗效问题仍是难题。基因修饰联合干细胞移植的出现为干细胞研究提供了新思路。目的：就现阶段用于心脏再生治疗的干细胞种类、治疗性基因的选择、移植载体与移植途径的探索及基因修饰干细胞在心血管治疗领域的临床应用进行概述。方法：应用计算机检索PubMed数据库中2006年1月至2013年12月关于干细胞的文章,在标题和摘要中以＂stem cells;genetic therapy;myocardial infarction;regenerative medicine;tissue construction＂为检索词进行检索。选择文章内容与干细胞有关者,同一领域文献则选择近期发表或发表在权威杂志文章。最终选择40篇文献进行综述。结果与结论：干细胞联合基因修饰疗法可显著增强移植后的疗效,骨髓间充质干细胞是目前应用最广泛的种子细胞之一,通过腺病毒及腺相关病毒介导的抗凋亡、促血管生成、抗炎症等基因修饰后的干细胞疗效将显著提高。基因修饰干细胞移植有潜力应用于包括心肌梗死在内的多种临床疾病,但其长期安全性仍有待进一步研究。     

The recombinant bifunctional protein αCD133–GPVI promotes repair of the infarcted myocardium in mice

Background:  Bone‐marrow‐derived progenitor cells are important in myocardial repair mechanisms following prolonged ischemia. Cell‐based therapy of diseased myocardium is limited by a low level of tissue engraftment. Objectives:  The aim of this study was the development of the bifunctional protein αCD133–glycoprotein (GP)VI as an effective treatment for supporting vascular and myocardial repair mechanisms. Results:  We have generated and characterized a bifunctional molecule (αCD133–GPVI) that binds both to the subendothelium of the injured microvasculature and to CD133⁺ progenitor cells with high affinity. αCD133–GPVI enhances progenitor cell adhesion to extracellular matrix proteins and differentiation into mature endothelial cells. In vivo studies showed that αCD133–GPVI favors adhesion of circulating progenitor cells to the injured vessel wall (intravital microscopy). Also, treatment of mice undergoing experimental myocardial infarction with αCD133–GPVI‐labeled progenitor cells reduces infarction size and preserves myocardial function. Conclusions:  The bifunctional trapping protein αCD133–GPVI represents a novel and promising therapeutic option for limiting heart failure of the ischemic myocardium.     

干细胞移植治疗缺血性心脏病：临床应用的可行性与安全性

背景：干细胞移植到受损的心脏组织,可以大量分化为心肌细胞,这项研究为缺血性心脏病治疗带来新的希望。目的：探讨干细胞移植治疗缺血性心脏病的可行性与安全性。方法：分析干细胞移植治疗缺血性心脏病安全性和可行性的多种试验方法。REPAIR-AMI试验是一项分析急性心肌梗死后即刻冠脉内移植骨髓祖细胞治疗效果的随机双盲、安慰剂对照的多中心研究;MAGICCell-3-DES试验是评价粒细胞集落刺激因子动员的干细胞疗法的安全性和冠脉内注射动员的外周血干细胞对急性心肌梗死和陈旧性心肌梗死的效果;BOOST试验是心肌梗死后经冠脉移植自体骨髓细胞的随机对照研究。PROTECT-CAD试验是一项随机、对照的直接将干细胞注入心肌治疗慢性缺血性心肌病的临床试验。结果与结论：干细胞移植可以改善左心室的收缩功能和舒张功能以及冠脉血流储备,相关研究也得到验证。对于干细胞移植治疗缺血性心脏病,可以增加左室射血分数,临床事件较少,在药物洗脱支架治疗的基础上,干细胞治疗并不增加再狭窄风险。干细胞移植治疗缺血性心脏病安全可行,未来还需要进行大样本、长时间的大规模多中心的随机对照研究,来进一步评价其疗效和风险。     

Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy

Molecular biologic techniques have a variety of applications in the study of ischemic heart disease, including roles in elucidating cardiac genetic changes resulting from ischemia as well as in developing therapeutic interventions to treat ischemic heart disease. This review describes recent studies documenting genetic changes associated with myocardial ischemia and infarction as well as those investigating the safety and effectiveness of gene therapy for stimulating angiogenesis, protecting the heart against reperfusion injury, and treating heart failure. Also discussed are future research directions, including the potential use of RNA interference and combined stem cell therapy and gene therapy for the treatment of cardiovascular disease.     

SDF-1α as a therapeutic stem cell homing factor in myocardial infarction

Myocardial infarction is associated with persistent muscle damage, scar formation and depressed cardiac performance. Recent studies have demonstrated the clinical significance of stem cell-based therapies after myocardial infarction with the aim to improve cardiac remodeling and function by inducing the reconstitution of functional myocardium and formation of new blood vessels. Stem cell homing signals play an important role in stem cell mobilization from the bone marrow to the ischemic cardiac environment and are therefore crucial for myocardial repair. To date, the most prominent stem cell homing factor is the chemokine SDF-1α/CXCL12. This protein was shown to be significantly upregulated in many experimental models of myocardial infarction and in patients suffering from ischemic cardiac diseases, suggesting the involvement in the pathophysiology of these disorders. A number of studies focused on manipulating SDF-1α and its receptor CXCR4 as central regulators of the stem cell mobilization process. Targeted expression of SDF-1α after myocardial infarction was shown to result in increased engraftment of bone marrow-derived stem cells into infarcted myocardium. This was accompanied by beneficial effects on cardiomyocyte survival, neovascularization and cardiac function. Thus, the SDF-1/CXCR4 axis seems to be a promising novel therapeutic approach to improve post-infarction therapy by attracting circulating stem cells to remain, survive and possibly differentiate in the infarct area. This review will summarize clinical trials of stem cell therapy in patients with myocardial infarction. We further discuss the basic findings about SDF-1α in stem cell recruitment and its therapeutic implications in experimental myocardial infarction.     

The Gap Between the Physiological and Therapeutic Roles of Mesenchymal Stem Cells

Several investigators have cultivated marrow stromal cells and have identified a population of mesenchymal stem cells (MSCs). These cells expand extensively in vitro and exhibit multilineage differentiation potential. The lack of MSC‐specific markers impedes identification of MSC functions. Further in vivo studies of these cells may elucidate the nature of MSCs. Although the nature of MSCs remains unclear, nonclonal stromal cultures are used as a source of putative MSCs for therapeutic purposes. Preclinical studies and clinical trials assumed that transplanted MSCs exert their effects through their differentiation properties or through the release of molecules that restore tissue functions and modulate immune cells. These studies reported contradictory results and failed to meet expectations. Thus, it is important to note that current protocols for MSC therapy are primarily based on the use of in vitro expanded nonclonal MSCs. Clearly defining the physiological features of in situ MSCs and the in vitro and in vivo properties of nonclonal cultures of stromal cells, which are often misidentified as pure stem cell cultures, may explain the reported failures of MSC therapy. This review will address these issues.     

Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Adult stem cells have shown great promise toward repairing infarcted heart and restoring cardiac function. Mesenchymal stem cells (MSCs), because of their inherent multipotent nature and their ability to secrete a multitude of growth factors and cytokines, have been used for cardiac repair with encouraging results. Preclinical studies showed that MSCs injected into infarcted hearts improve cardiac function and attenuate fibrosis. Although stem cell transplantation is a promising therapeutic option to repair the infarcted heart, it is faced with a number of challenges, including the survival of the transplanted cells in the ischemic region, due to excessive oxidative stress present in the ischemic region. The objective of this study was to determine the effect of Carvedilol (Carv), a nonselective β-blocker with antioxidant properties, on the survival and engraftment of MSCs in the infarcted heart. MSCs were subjected to a simulated host-tissue environment, similar to the one present in the infarcted myocardium, by culturing them in the presence of hydrogen peroxide (H(2)O(2)) to induce oxidative stress. MSCs were treated with 2.5 μM Carv for 1 h in serum-free medium, followed by treatment with H(2)O(2) for 2 h. The treated cells exhibited significant protection against H(2)O(2)-induced cell death versus untreated controls as determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays. Likewise, transplantation of MSCs after permanent left coronary artery ligation and treatment of animals after myocardial infarction (MI) with Carv (5 mg/kg b.wt.) led to significant improvement in cardiac function, decreased fibrosis, and caspase-3 expression compared with the MI or MSC-alone groups.     

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.     

The effect of serum on the proliferation of bone marrow‐derived mesenchymal stem cells from aged donors and donors with or without chronic heart failure

Many clinical studies of regenerative medicine using bone marrow‐derived mesenchymal stem cells (MSCs) have been conducted globally. We initiated clinical studies using MSCs in 2001 and have now treated over 100 cases with patients aged 0–92 years. In a few cases involving patients with chronic heart failure (CHF), we observed that MSCs proliferated poorly. This contrasts with cell therapy studies wherein MSCs of patients with CHF were used for treatment. The effects of serum on the proliferation of MSCs from donors with normal heart function and with CHF have not been reported. Moreover, whether cell therapy is effective for elderly patients remains uncertain. Therefore, characterization of MSCs from aged donors and/or donors with CHF is urgently required. We retrospectively analysed the population doubling times (PDTs) of MSCs between the first and second passages. Although we had data for many samples of well‐expanded MSCs from aged donors, a positive correlation was observed between donor age and PDT. A trend towards reduced variance in PDTs was observed in MSCs supplemented with fetal bovine serum (FBS) compared with those supplemented with autologous serum. When autologous serum was used, the average PDT of MSCs from donors with CHF was significantly longer than that of MSCs from donors without CHF. In contrast, when FBS was used, similar PDTs were observed in MSCs from donors with and without CHF. Thus, FBS promotes MSC expansion even from donors with CHF and MSC‐based regenerative medicine might be feasible even for elderly patients. Copyright © 2016 John Wiley & Sons, Ltd.     

Cardiac Cell Repair Therapy: A Clinical Perspective

From bone marrow transplants 5 decades ago to the most recent stem cell—derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the “broken” heart.GCSF = granulocyte colony-stimulating factor; HSC = hematopoietic stem cell; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MSC = mesenchymal stem cell

It''s easy to be excited about stem cell research.Deborah J. Sweet, PhD¹Editor and Executive Editor, Cell Press

This quotation from the editor of the inaugural issue of the journal Cell Stem Cell seems apt, given what we already know about the potential for stem cells to play a pivotal therapeutic role in a diverse group of diseases. Some of these treatments, such as bone marrow transplant, have been standards of care for years, but the promise of extending stem cell therapy into other organ systems, including the heart, has understandably generated enthusiasm as well as controversy. Regardless of whether one is a skeptic, an active part of the burgeoning community of stem cell investigators, or an interested clinician, the field is gathering momentum, and it behooves us all to become familiar with the concepts and the lexicon of cell repair therapy as the pace of translational research accelerates.Accordingly, this review of cardiac cell repair therapy aims to provide a clinical perspective on and outline of the scientific issues underpinning both experimental and clinical studies, highlight the results of randomized controlled clinical trials and the design of future trials, and introduce ethical and philosophical issues of concern.Cardiac repair can be considered as the outcome of 3 major processes: replacement (tissue transplant), rejuvenation or restoration (activation of resident cardiac stem cells or other stem cells via paracrine or autocrine mechanisms; modulation of apoptosis, inflammation, angiogenesis, or metabolism), and regeneration (progenitor or stem cell engraftment forming differentiated myocytes).^2,3 These different entities may be interlinked in that modulation of myocardial injury may also benefit subsequent therapy directed at myocardial regeneration.²     

Autologous bone marrow stem cell therapy for the ischemic myocardium during coronary artery bypass grafting

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Especially the treatment of ischemic heart disease challenges physicians despite recent advances in medical and operative strategies. Due to the considerable developments in regenerative medicine cell‐based treatment for ischemic heart disease has attracted great interest in the last decade. Numerous experimental and clinical approaches employing stem cell treatment from various sources and using different methods of cell delivery have shown improvement in cardiac function after acute or chronic ischemic jeopardy. In this report we will focus on our long‐term experience on the safety of bone marrow derived CD133⁺ stem cell transplantation with concomitant coronary artery bypass surgery and provide an overview of the current knowledge on utilizing cell‐based treatment for ischemic heart disease.     

Cardiac cell therapy: a treatment option for cardiomyopathy

Cardiomyopathy is a common clinical disorder affecting the heart muscle. This disease process frequently leads to congestive heart failure and will often progress to end-stage heart failure. Present standard of care treatment options for cardiomyopathy include medical management, lifestyle changes, and surgical procedures including left ventricular assist devices as a destiny therapy or bridging to heart transplantation. Even despite advances in drug therapy, mechanical assist devices, and organ transplantation, more than half of the persons with cardiomyopathy will die within 5 years of diagnosis. Small uncontrolled clinical trials have demonstrated cardiac stem cells as a treatment option for cardiomyopathy. The theory for the individual or combined mechanism of action for stem cells includes (1) transdifferentiation to blood vessels or myocardium, (2) fusion with the native dysfunctional myocytes to augment function, and (3) homing that may be a systemic or panacrine response for recruiting other cells, and growth factors to help improve oxygen delivery and myocardial function. The field of cardiac cell therapy is rapidly progressing to gather more data with intermediate-size, double-blinded trials that will demonstrate the safety and efficacy of cell therapy.     

Engineering cell platforms for myocardial regeneration

INTRODUCTION: Various engineered 'cell-platforms' have been reported in recent years for the possible treatment of myocardial infarction (MI) and end-stage heart failure. These engineered platforms rely on two key factors: cells and/or biomaterial scaffolds for the regeneration of the infarcted heart tissue. AREAS COVERED: Two major cell-platform approaches are described and broadly categorized as 'injectable cell platforms' and 'patch-based cell platforms'. The recent advancements in these cell-platforms in terms of their relative successes in-vivo as well as their clinical feasibility are summarized. Natural as well as synthetic scaffolds, with or without the cellular component, are compared with cell based therapy alone. This review focuses on achievements, as well as the gaps that are presently checking any progress towards producing clinically relevant panacea for myocardial regeneration. EXPERT OPINION: Cardiac and induced pluripotent stem cells will probably be the focus of future research. The combined cell-biomaterial scaffold therapy is superior to cell therapy alone. Nevertheless, encouraging pre-clinical successes have limited translation into clinical practice due to limited cell survival post transplantation, inadequate construct thicknesses for human-sized hearts and the traditional use of 'flat (2D) tissue culture' techniques. The development of complementary dynamic 3D cultivation platforms will probably lead to improved outcomes and enable fast screening of various therapeutic approaches.