Migration of Resident Cardiac Stem Cells in Myocardial Infarction

Ischemic heart disease is a major cause of morbidity and mortality worldwide. Stem cell‐based therapy, which aims to restore cardiac structure and function by regeneration of functional myocardium, has recently been proposed as a novel alternative treatment modality. Resident cardiac stem cells (CSCs) in adult hearts are a key cell type under investigation. CSCs have been shown to be able to repair damaged myocardium and improve myocardial function in both human and animal studies. This approach relies not only on the proliferation of the CSCs, but also upon their migration to the site of injury within the heart. Here, we briefly review reported CSC populations and discuss signaling factors and pathways required for the migration of CSCs. Anat Rec, 2013. © 2012 Wiley Periodicals, Inc.     

脂肪来源细胞在缺血性心脏病中的应用

 脂肪来源细胞（褐色脂肪来源细胞、脂肪干细胞和去分化脂肪细胞）可分化成心肌样细胞,移植后可改善心梗后心功能,降低心室重塑,有可能成为最有潜力的治疗缺血性心脏病的干细胞来源。     

Cardiac Cell Therapy: Boosting Mesenchymal Stem Cells Effects

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and several clinical trials have evaluated their clinical efficacy in myocardial infarction. However, the beneficial effects of MSC in humans are limited due to poor engraftment and survival of these cells, therefore ways to overcome these obstacles should improve efficacy. Different strategies have been used, such as genetically modifying MSC, or preconditioning the cells with factors that potentiate their survival and therapeutic mechanisms. In this review we compile the most relevant approaches used to improve MSC therapeutic capacity and to understand the molecular mechanisms involved in MSC mediated cardiac repair.     

干细胞移植治疗心肌坏死的基础与临床研究

干细胞治疗心肌坏死是一种新的很有前景的治疗手段,但其机制尚不十分清楚。我国目前临床研究发现干细胞移植可以明显改善急性心肌梗死及梗死后心衰心脏功能,但由于关于干细胞移植的安全性还没有定论,因此还需慎重对待。     

Stem cell therapy: a hope for dying hearts

The restoration of functional myocardium following heart failure still remains a formidable challenge among researchers. Irreversible damage caused by myocardial infarction is followed by left ventricular remodeling. The current pharmacologic and interventional strategies fail to regenerate dead myocardium and are usually insufficient to meet the challenge caused by necrotic cardiac myocytes. There is growing evidence, suggesting that the heart has the ability to regenerate through the activation of resident cardiac stem cells or through the recruitment of a stem cell population from other tissues such as bone marrow. These new findings belie the earlier conception about the poor regenerating ability of myocardial tissue. Stem cell therapy is a promising new approach for myocardial repair. However, it has been limited by the paucity of cell sources for functional human cardiomyocytes. Moreover, cells isolated from different sources exhibit idiosyncratic characteristics including modes of isolation, ease of expansion in culture, proliferative ability, characteristic markers, etc., which are the basis for several technical manipulations to achieve successful engraftment. Clinical trials show some evidence for the successful integration of stem cells of extracardiac origin in adult human heart with an improved functional outcome. This may be attributed to the discrepancies in the methods of detection, study subject selection (early or late post transplantation), presence of inflammation, and false identification of infiltrating leukocytes. This review discusses these issues in a comprehensive manner so that their physiological significance in animal as well as in human studies can be better understood.     

Combining adult stem cells and polymeric devices for tissue engineering in infarcted myocardium

An increasing number of studies in cardiac cell therapy have provided encouraging results for cardiac repair. Adult stem cells may overcome ethical and availability concerns, with the additional advantages, in some cases, to allow autologous grafts to be performed. However, the major problems of cell survival, cell fate determination and engraftment after transplantation, still remain. Tissue-engineering strategies combining scaffolds and cells have been developed and have to be adapted for each type of application to enhance stem cell function. Scaffold properties required for cardiac cell therapy are here discussed. New tissue engineering advances that may be implemented in combination with adult stem cells for myocardial infarction therapy are also presented. Biomaterials not only provide a 3D support for the cells but may also mimic the structural architecture of the heart. Using hydrogels or particulate systems, the biophysical and biochemical microenvironments of transplanted cells can also be controlled. Advances in biomaterial engineering have permitted the development of sophisticated drug-releasing materials with a biomimetic 3D support that allow a better control of the microenvironment of transplanted cells.     

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.     

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.     

Thérapie cellulaire en phase aiguë d’infarctus du myocarde

Despite important progress in cardiology, acute myocardial infarction (AMI) is the major cause of congestive heart failure and subsequent mortality. The rationale for cell therapy to be administered after AMI is derived from the assumption that given the insufficient regeneration in the injured heart tissue, stem cells from the bone marrow may be able to replace or repair damaged vascular and cardiac tissue. Results of the first phase I clinical trials using bone marrow stem/progenitor cell therapy for AMI were published in 2002 to 2004. Although not designed to test the efficacy of the intervention, the initial trials indicated a promising improvement in a number of clinical outcomes and cardiac function and suggested the intervention was safe. Recently, randomized controlled trials of cardiac cell therapy for AMI were published, with mixed results. A meta-analysis including 13 trials with a total of 811 participants showed an improved left ventricular ejection fraction by 2.99%. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy on clinical outcomes.     

New era of cardiac stem cell therapy in heart failure

Despite of plethora of reports on stem cell transplantation leading to neovascularization in infarct models, whether sustaining clinical benefit in post-myocardial infarction patients is manifested by myocyte repair remains unclear. Cardiac muscle regeneration in adult heart is thought to occur through the mobilization and differentiation of mesenchymal stem cells in bone marrow origin, however, recent studies have suggested that substantial cardiac stem cells may exist in the heart itself, repopulating the damaged cardiac muscle during injury or aging processes. The implications of cardiac stem cells-based myocyte plasticity have recently begun to define in human heart, neither arisen from bone marrow nor circulating precursors. Introduction of cardiac stem cells may improve myocardial function, but several hurdles exist and should be coaxed far beyond the clinical application of cardiac regenerative therapies. On-going investigations may lead to the discovery of mediators of cardiac stem cells migration, proliferation and differentiation that, in turn, might result in the mending of the broken heart after injury.     

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。     

Chemical and physical regulation of stem cells and progenitor cells: potential for cardiovascular tissue engineering

The field of cardiovascular tissue engineering has experienced tremendous advances in the past several decades, but the clinical reality of engineered heart tissue and vascular conduits remains immature. Stem cells and progenitor cells are promising cell sources for engineering functional cardiovascular tissues. To realize the therapeutic potential of stem cells and progenitor cells, we need to understand how microenvironmental cues modulate and guide stem cell differentiation and organization. This review describes the current understanding of the chemical and physical regulation of embryonic and adult stem cells for potential applications in cardiovascular repair, focusing on cardiac therapies after myocardial infarction and the engineering of vascular conduits.     

Cardiac stem cells and mechanisms of myocardial regeneration

This review discusses current understanding of the role that endogenous and exogenous progenitor cells may have in the treatment of the diseased heart. In the last several years, a major effort has been made in an attempt to identify immature cells capable of differentiating into cell lineages different from the organ of origin to be employed for the regeneration of the damaged heart. Embryonic stem cells (ESCs) and bone marrow-derived cells (BMCs) have been extensively studied and characterized, and dramatic advances have been made in the clinical application of BMCs in heart failure of ischemic and nonischemic origin. However, a controversy exists concerning the ability of BMCs to acquire cardiac cell lineages and reconstitute the myocardium lost after infarction. The recognition that the adult heart possesses a stem cell compartment that can regenerate myocytes and coronary vessels has raised the unique possibility to rebuild dead myocardium after infarction, to repopulate the hypertrophic decompensated heart with new better functioning myocytes and vascular structures, and, perhaps, to reverse ventricular dilation and wall thinning. Cardiac stem cells may become the most important cell for cardiac repair.     

Hyperhomocysteinemia inhibited cardiac stem cell homing into the peri-infarcted area post myocardial infarction in rats

Background

Hyperhomocysteinemia (HHcy) has been reported as an independent risk factor for coronary artery disease; however it is not clear regarding the action of HHcy on the homing of cardiac stem cells (CSCs) to the damaged myocardium and the consequent CSCs-mediated cardiac repair post myocardial infarction.

Methods

Sprague–Dawley (SD) rats were divided into 4 groups. HHcy was induced in the rats by a 6-week high-methionine diet. Rat heart MI model was developed by left coronary artery ligation. Immunofluorescence was used to examine the CSCs migration in vivo via injecting BrdU-labeled CSCs into AV-groove followed by a coronary ligation. Immunohistochemistry, western blot and ELISA analysis were carried out to detect the expression of stem cell factor (SCF) protein, and RT-PCR was conducted for the expression of SCF mRNA.

Results

On day 5 of MI model creation, accumulation of CSCs was significantly increased in the peri-infarcted area by the non-hyperhomocysteinemic rats, which led to an improvement of cardiac function at 3 weeks after MI. however, the accumulation of CSCs was markedly decreased by the hyperhomocysteinemic rats followed with the decline of cardiac function. SCF expression was also significantly decreased in the peri-infarcted area by the hyperhomocysteinemic rats compared to the non-hyperhomocysteinemic rats. The experiments in vitro confirmed that homocysteine (Hcy) decreased SCF expression via inhibition of TNF-α-induced activity of NF-κB, further reduced the migration of CSCs.

Conclusion

It demonstrated that hyperhomocysteinemia may significantly contribute to restrain CSCs-mediated cardiac repair by reducing SCF-induced homing of CSCs.     

心脏干细胞的研究与进展

背景：大量研究证明,哺乳动物心脏中存在心脏自身干细胞,参与心脏的自我更新和内源性修复。 目的：就心脏干细胞的来源、分类、特征及心脏病治疗等方面进行综述。 方法：由第一作者应用计算机检索PubMed数据库2000-01/2010-12有关心脏干细胞的来源、分化、特征及其在心肌再生方面的文章,检索词为“Cardiac stem cell”,包括临床研究和基础研究,排除重复研究和Meta 分析,共保留32篇文献进行综述。 结果与结论：心脏干细胞是一类存在于心脏组织内能够自我更新及克隆增殖的干细胞,它能够分化为心肌细胞、内皮细胞,参与心脏损伤修复,改善心功能。现已能够通过体外分离培养扩增后移植入动物心脏内,为下一步在临床上应用于人体打下了基础。但成体心脏干细胞自身的稳态平衡和动态变化,及其向心脏功能细胞分化需经历哪些具体过程,有哪些影响因素及如何调控等还不太清楚,需要继续研究以进一步证实。     

Clinical applications of stem cell therapy for regenerating the heart

An immediate reperfusion therapy after acute myocardial infarction (AMI) is a prerequisite to prevent further cardiac damage and minimize ventricular remodelling. Although a rigorous and sophisticated set of therapeutic procedure has been applied in the disease management, mortality rate has yet unchanged during the last twenty years. This fact necessitates an alternative or adjuvant therapy that is critically safe and capable of repairing the injured vascular as well as regenerating the infarcted myocardium without omitting the ethical considerations. Stem cell therapy could be the answer. It has gained major basic and clinical research interest, ever since its discovered potential to repair the injured vascular in 1997. Multiple cell types across lineages have been shown to be able to transdifferentiate into mature functioning cardiomyocytes either in vitro through similar phenotypical and genotypical characteristics or in vivo by regenerating the infarcted myocardium and improve contractile function. Although the exact repairing mechanisms are still in a major debate, numerous clinical trials have demonstrated favorable effects toward the use of autologous stem cells in AMI patients with considerably low side effects. Despite the relatively novel discovery, stem cell therapy offers a promising prospect to confer a better protection, prevent later complications, and perhaps reduce the mortality among patients with ischemic heart disease. This ultimate outcome would likely be achieved through a stringent and coordinated of either basic and clinical research.     

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.     

In Vitro and In Vivo Cardiomyogenic Differentiation of Amniotic Fluid Stem Cells

Cell therapy has developed as a complementary treatment for myocardial regeneration. While both autologous and allogeneic uses have been advocated, the ideal candidate has not been identified yet. Amniotic fluid-derived stem (AFS) cells are potentially a promising resource for cell therapy and tissue engineering of myocardial injuries. However, no information is available regarding their use in an allogeneic context. c-kit-sorted, GFP-positive rat AFS (GFP-rAFS) cells and neonatal rat cardiomyocytes (rCMs) were characterized by cytocentrifugation and flow cytometry for the expression of mesenchymal, embryonic and cell lineage-specific antigens. The activation of the myocardial gene program in GFP-rAFS cells was induced by co-culture with rCMs. The stem cell differentiation was evaluated using immunofluorescence, RT-PCR and single cell electrophysiology. The in vivo potential of Endorem-labeled GFP-rAFS cells for myocardial repair was studied by transplantation in the heart of animals with ischemia/reperfusion injury (I/R), monitored by magnetic resonance imaging (MRI). Three weeks after injection a small number of GFP-rAFS cells acquired an endothelial or smooth muscle phenotype and to a lesser extent CMs. Despite the low GFP-rAFS cells count in the heart, there was still an improvement of ejection fraction as measured by MRI. rAFS cells have the in vitro propensity to acquire a cardiomyogenic phenotype and to preserve cardiac function, even if their potential may be limited by poor survival in an allogeneic setting.     

Heart repair and stem cells

Of the medical conditions currently being discussed in the context of possible treatments based on cell transplantation therapy, few have received more attention than the heart. Much focus has been on the potential application of bone marrow-derived cell preparations, which have already been introduced into double-blind, placebo-controlled clinical trials. The consensus is that bone marrow may have therapeutic benefit but that this is not based on the ability of bone marrow cells to transdifferentiate into cardiac myocytes. Are there potential stem cell sources of cardiac myocytes that may be useful in replacing those lost or dysfunctional after myocardial infarction? Here, this question is addressed with a review of the recent literature.