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;MAGIC Cell-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。     

Cardiac Stem Cells and their Roles in Myocardial Infarction

Myocardial infarction leads to loss of cardiomyocytes, scar formation, ventricular remodeling and eventually deterioration of heart function. Over the past decade, stem cell therapy has emerged as a novel strategy for patients with ischemic heart disease and its beneficial effects have been demonstrated by substantial preclinical and clinical studies. Efficacy of several types of stem cells in the therapy of cardiovascular diseases has already been evaluated. However, repair of injured myocardium through stem cell transplantation is restricted by critical safety issues and ethic concerns. Recently, the discovery of cardiac stem cells (CSCs) that reside in the heart itself brings new prospects for myocardial regeneration and reconstitution of cardiac tissues. CSCs are positive for various stem cell markers and have the potential of self-renewal and multilineage differentiation. They play a pivotal role in the maintenance of heart homeostasis and cardiac repair. Elucidation of their biological characteristics and functions they exert in myocardial infarction are very crucial to further investigations on them. This review will focus on the field of cardiac stem cells and discuss technical and practical issues that may involve in their clinical applications in myocardial infarction.     

Cardiac stem cells

Augmentation of myocardial performance in experimental models of therapeutic infarction and heart failure has been achieved by the transplantation of exogenous cells into damaged myocardium, a procedure known as cellular cardiomyoplasty (CCM). Historically, a wide range of cell types have been used for CCM, including rat and human fetal ventricular myocytes, but the availability of human fetal donor cells for clinical purposes is limited. The quest for suitable alternative donor cells has prompted research into the use of both embryonic stem (ES) cells and adult somatic stem cells, but the optimal choice of donor cell source is not yet known. Recently, there has been a growing body of evidence that multipotent somatic stem cells in adult bone marrow exhibit tremendous functional plasticity and can reprogramme in a new environmental tissue niche to give rise to cell lineages specific for the new organ site. This phenomenon has made a huge impact on myocardial biology and has captured the imagination of scientists who have recently discovered that multipotent adult bone marrow haematopoeitic stem cells and mesenchymal stem cells can repopulate infarcted rodent myocardium and differentiate into both cardiomyocytes and new blood vessels. These data, coupled with the identification of a putative primitive cardiac stem cell population in the adult human heart, may pave the way for novel therapeutic modalities for enhancing myocardial performance and treating end-stage cardiac disease.     

自体骨髓干细胞移植治疗心力衰竭的研究进展

细胞移植已为病损心脏细胞重建及衰竭心脏功能恢复提供了一种全新的治疗方法。骨髓干细胞具有自我更新、定向分化成为包括心肌细胞等多种组织细胞的潜能,其增殖分化能力能持续终生,已成为细胞移植治疗心力衰竭的主要细胞源。本文就自体骨髓干细胞治疗心力衰竭可行性、与其他移植细胞相比较的优势、临床应用现状及目前问题与展望作一综述。     

Stem cells for heart cell therapies

Myocardial infarction-induced heart failure is a prevailing cause of death in the United States and most developed countries. The cardiac tissue has extremely limited regenerative potential, and heart transplantation for reconstituting the function of damaged heart is severely hindered mainly due to the scarcity of donor organs. To that end, stem cells with their extensive proliferative capacity and their ability to differentiate toward functional cardiomyocytes may serve as a renewable cellular source for repairing the damaged myocardium. Here, we review recent studies regarding the cardiogenic potential of adult progenitor cells and embryonic stem cells. Although large strides have been made toward the engineering of cardiac tissues using stem cells, important issues remain to be addressed to enable the translation of such technologies to the clinical setting.     

Stem cell differentiation: cardiac repair

Cellular transplantation has been employed for several years to deliver donor cardiomyocytes to normal and injured hearts. Recent reports of a variety of stem cells with apparent cardiomyogenic potential have raised the possibility of cell transplantation-based therapeutic interventions for heart disease. Here we review the preclinical studies demonstrating that intracardiac transplantation of skeletal myoblasts, cardiomyocytes and cardiomyogenic stem cells is feasible. In addition, recent clinical studies of skeletal myoblast and adult stem cell transplantation for heart disease are discussed.     

Bone marrow-derived stem cell therapy in ischemic heart disease

Since the first experiments of cell transplantation into the heart were performed in the early 1990s, the identification of adult stem cells has triggered attempts to regenerate damaged heart tissue by cellular transplantation. Until recently, a multitude of adult stem or progenitor cells from various tissues have been proposed to meet this end. Bone marrow in particular has emerged as the most promising source for stem and progenitor cells because, besides being the organ of hematopoietic maintenance, it contains a complex assortment of stem and progenitor cells. A large body of provocative experimental evidence for vascular and myocardial regeneration by these cells has generated further enthusiasm for their use. However, many questions remain unanswered in this new field of research regarding the therapeutic potential and the mechanisms responsible for the observed therapeutic effects. In this review, the authors discuss the therapeutic capacity of currently available representative bone marrow-derived stem and progenitor cells for treating ischemic heart diseases.     

Cell delivery in cardiac regenerative therapy

There is a growing interest in the clinical application of stem cells as a novel therapeutic approach for treatment of myocardial infarction and prevention of subsequent heart failure. Transplanted stem cells improve cardiac functions through multiple mechanisms, which include but are not limited to promoting angiogenesis, replacing dead cardiomyocytes, modulating cardiac remodeling. Most of the results obtained so far are exciting and very promising, spawning an increasing number of clinical trials recently. However, many problems still remain to be resolved such as the best delivery method for transplantation of cells to the injured myocardium and the issue of how to optimize the delivery of targeted cells is of exceptional clinical relevance. In this review, we focus on the different delivery strategies in cardiac regenerative therapy, as well as provide a brief overview of current clinical trials utilizing cell-based therapy in patients with ischemic heart disease.     

Multipotent stem cells in cardiac regenerative therapy

The potential for stem cells to ameliorate or cure heart diseases has galvanized a cadre of cardiovascular translational and clinical scientists to take a 'first-in-man' approach using autologous stem cells from a variety of tissues. However, recent clinical trial data show that when these cells are given by intracoronary infusion or direct myocardial injection, limited improvement in heart function occurs with no evidence of cardiomyogenesis. These studies illustrate the great need to understand the logic of cell-lineage commitment and the principles of cardiac differentiation. Recent identification of stem/progenitor cells of embryological origin with intrinsic competence to differentiate into multiple lineages within the heart offers new possibilities for cardiac regeneration. When combined with developments in nuclear reprogramming and provided that tumor risks and other challenges of embryonic cell transplantation can be overcome, the prospect of achieving autologous, cardiomyogenic, stem cell-based therapy may be within reach.     

Pre-transplantation Specification of Stem Cells to Cardiac Lineage for Regeneration of Cardiac Tissue

Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration.     

胎儿脐血间充质干细胞治疗大鼠急性心肌梗死

背景：胎儿脐血间充质干细胞对病变心肌有修复和再生能力,胎儿脐血间充质干细胞移植是治疗心肌梗死的一种新途径。 目的：探讨胎儿脐血间充质干细胞移植治疗大鼠心肌梗死的效果。 方法：选取32只大鼠结扎左冠状动脉前降支制作心肌梗死动物模型,随机等分为移植组和梗死组,从胎儿脐血中分离培养脐血间充质干细胞,制备脐血间充质干细胞悬液,对移植组大鼠进行脐血间充质干细胞移植。 结果与结论：胎儿脐血间充质干细胞在体外可以被成功分离培养;与梗死组相比,移植组大鼠心肌梗死边缘区的微血管密度、左室收缩末压、左室内压最大上升和下降速率显著增加(P < 0.05),左室舒张末压显著下降(P < 0.05),心电图情况稍有好转。表明胎儿脐血间充质干细胞治疗心肌梗死大鼠可以促进心肌血管再生,改善心脏功能。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Cardiac cell therapy: the next (re)generation

Heart failure remains one of the main causes of morbidity and mortality in the Western world. Current therapies for myocardial infarction are mostly aimed at blocking the progression of the disease, preventing detrimental cardiac remodeling and potentiating the function of the surviving tissue. In the last decade, great interest has arisen from the possibility to regenerate lost tissue by using cells as a therapeutic tool. Different cell types have been tested in animal models, including bone marrow-derived cells, myoblasts, endogenous cardiac stem cells, embryonic cells and induced pluripotent stem cells. After the conflicting and often inconsistent results of the first clinical trials, a step backward needs to be performed, to understand the basic biological mechanisms underlying spontaneous and induced cardiac regeneration. Current studies aim at finding new strategies to enhance cellular homing, survival and differentiation in order to improve the overall outcome of cellular cardiomyoplasty     

Hematopoietic stem and progenitor cell trafficking

Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients.     

Human pancreatic islet-derived progenitor cell engraftment in immunocompetent mice

The potential for the use of stem/progenitor cells for the restoration of injured or diseased tissues has garnered much interest recently, establishing a new field of research called regenerative medicine. Attention has been focused on embryonic stem cells derived from human fetal tissues. However, the use of human fetal tissue for research and transplantation is controversial. An alternative is the isolation and utilization of multipotent stem/progenitor cells derived from adult donor tissues. We have previously reported on the isolation, propagation, and partial characterization of a population of stem/progenitor cells isolated from the pancreatic islets of Langerhans of adult human donor pancreata. Here we show that these human adult tissue-derived cells, nestin-positive islet-derived stem/progenitor cells, prepared from human adult pancreata survive engraftment and produce tissue chimerism when transplanted into immunocompetent mice either under the kidney capsule or by systemic injection. These xenografts seem to induce immune tolerance by establishing a mixed chimerism in the mice. We propose that a population of stem/progenitor cells isolated from the islets of the pancreas can cross xenogeneic transplantation immune barriers, induce tissue tolerance, and grow.     

The Potential of Stem Cells in the Treatment of Cardiovascular Diseases

Although the adult mammalian heart was once believed to be a post-mitotic organ without any capacity for regeneration, recent findings have challenged this dogma. A modified view assigns to the mammalian heart a measurable capacity for regeneration throughout life. The ultimate goals of the cardiac regeneration field have been pursued by multiple strategies, including understanding the developmental biology of cardiomyocytes and cardiac stem and progenitor cells, applying chemical genetics, and engineering biomaterials and delivery methods that facilitate cell transplantation. Successful stimulation of endogenous regenerative capacity in injured adult mammalian hearts can benefit from studies of natural cardiac regeneration.     

自体心脏干细胞移植治疗缺血性心肌病的进展

背景：药物、介入或外科治疗均不能从根本上解决心脏缺血梗死后心肌细胞丧失问题。大量研究结果显示自体心脏干细胞移植治疗缺血性心肌病安全可行,可减少梗死瘢痕面积、改善心室重构、提高心脏功能。目前自体心脏干细胞移植治疗缺血性心肌病已进入临床试验阶段。 目的：综述近年国内外自体心脏干细胞移植治疗缺血性心肌病的研究进展。 方法：第一作者应用计算机检索1998年1月至2012年4月PubMed数据库、中国期刊全文数据库相关文章,英文检索词“autologous, cardiac stem cells, ischemic cardiomyopathy, transplantation,treatment”;中文检索词“自体,心脏干细胞,缺血性心肌病,移植,治疗”。共检索到82篇相关文献,57篇文献符合纳入标准。 结果与结论：经过大量小动物实验和大型动物的前临床实验准备阶段,目前自体心脏干细胞移植治疗缺血性心肌病已经进入临床试验阶段,初步临床试验结果显示自体心脏干细胞移植治疗缺血性心肌病安全、可行、有效。从心脏中分离的心脏干细胞移植到自体缺血梗死的心脏,可以分化生成心肌细胞、内皮细胞、平滑肌细胞,抑制心室重构,改善心脏收缩、舒张功能。相对于其他来源的干细胞移植治疗,自体心脏干细胞移植治疗缺血性心肌病无免疫源性,不存在免疫排斥反应;不存在伦理问题;其趋向分化成心脏细胞系,成瘤率低,相对安全。自体心脏干细胞移植为缺血性心肌病的治疗提供了一条新的途径,有更高的临床应用价值。但目前开展的临床试验较少,观测时间不够长,缺少多中心大样本量的临床试验等,这些都需要进一步研究探索。     

Stem cells: new cell source for myocardial constructs tissue engineering

Cardiovascular diseases like myocardial infarction, complex congenital heart disease, and subsequent heart failure are a leading cause of morbidity and mortality. Recent advances in tissue engineering arise to address the lack of available tissues and organs for transplantation because cells alone are not capable of recreating complex tissues upon transplantation. Consequently, a very promising approach to repair large scar areas and congenital heart defects may be the use of tissue engineering, in which cells are seeded in three-dimensional matrices of biodegradable polymers to form myocardial constructs. In recent years, there has been a tremendous increase in the understanding of stem cell biology. Stem cells have clonogenic and self-renewing capabilities, and under certain conditions, can differentiate into multiple cell lineages. Recent studies have shown that stem cells can be isolated from a wide variety of tissues, including bone marrow, peripheral blood, muscle, and adipose tissue. We hypothesize that tissue-engineered myocardial constructs with stem cells may fulfill the requirements of native heart muscle and, in the long run, may allow replacement of the injured heart and repair of congenital cardiac defects possible.     

Criticality of the biological and physical stimuli array inducing resident cardiac stem cell determination

The replacement of injured cardiac contractile cells with stem cell-derived functionally efficient cardiomyocytes has been envisaged as the resolutive treatment for degenerative heart diseases. Nevertheless, many technical issues concerning the optimal procedures to differentiate and engraft stem cells remain to be answered before heart cell therapy could be routinely used in clinical practice. So far, most studies have been focused on evaluating the differentiative potential of different growth factors without considering that only the synergistic cooperation of biochemical, topographic, chemical, and physical factors could induce stem cells to adopt the desired phenotype. The present study demonstrates that the differentiation of cardiac progenitor cells to cardiomyocytes does not occur when cells are challenged with soluble growth factors alone, but requires strictly controlled procedures for the isolation of a progenitor cell population and the artifactual recreation of a microenvironment critically featured by a fine-tuned combination of specific biological and physical factors. Indeed, the scaffold geometry and stiffness are crucial in enhancing growth factor differentiative effects on progenitor cells. The exploitation of this concept could be essential in setting up suitable procedures to fabricate functionally efficient engineered tissues. Disclosure of potential conflicts of interest is found at the end of this article.     

脐血干细胞移植治疗心肌梗死的作用与机制

背景：多项基础和临床研究表明,干细胞移植可以改善心肌梗死后心力衰竭患者的心脏功能。 目的：总结脐血干细胞移植治疗心肌梗死的的作用与机制。 方法：由第一作者检索2000/2009 PubMed数据库及CNKI、万方数据库有关脐血干细胞移植治疗心肌梗死基础研究方面的文献。 结果与结论：干细胞移植在治疗急性心肌梗死方面已表现出传统治疗方法无法比拟的优势,而目前一系列基础研究证实人脐血干细胞有望成为更为理想的细胞源,但因其尚处于探索性研究阶段,仍有许多问题有待解决,诸如人脐血干细胞的体外分离、培养,最适宜的移植治疗时间,最有利的移植途径,最佳的移植数量,移植细胞的存活率如何,移植后能否分化为心肌细胞,分化程度如何以及其疗效和安全性等。     

The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment

One challenge of cellular cardiomyoplasty for myocardial infarction (MI) is how to improve MI microenvironment to facilitate stem cell engraftment, survival and homing for myocardial repair. The application of injectable hydrogels is an effective strategy. However, it has not been thoroughly investigated on the role of the injectable scaffolds, in improving MI microenvironment, providing space and guidance for cell survival, engraftment and homing. We explored an injectable chitosan hydrogel for stem cell delivery into ischemic heart and investigated the beneficial effects and mechanisms of the hydrogel. In vitro, H(2)O(2)-treatment was used to mimic reactive oxygen species (ROS) microenvironment. The influence of ROS and protection of chitosan components on adipose-derived mesenchymal stem cells (ADSCs) was analyzed too. In vivo, MI was induced by the left anterior descending artery ligation in SD rats. PBS, chitosan hydrogel, ADSC/PBS and ADSC/chitosan hydrogel were injected into the border of infracted hearts respectively. Multi-techniques were used to assess the beneficial effects of chitosan hydrogel after transplantation. We observed that ROS generated by ischemia would impair ADSC adhesion molecules, including integrin-related adhesion molecules integrin αV and β1, focal adhesion-related molecules p-FAK and p-Src, and corresponding ligands of host myocardium ICAM1 and VCAM1. Chitosan hydrogel could rescue these molecules through ROS scavenging and recruit key chemokine for stem cell homing, such as SDF-1. The results suggest that chitosan hydrogel could improve MI microenvironment, enhance stem cell engraftment, survival and homing in ischemic heart through ROS scavenging and chemokine recruitment, contributing to myocardial repair.