Bone-marrow stem cells as a source for cell therapy

Bone marrow stroma contains a subgroup of cells which can be guided in vitro to differentiate, and express cardiomyocyte phenotype. In vivo, these cells can become cardiomyocytes when implanted into the myocardium, in response to signals from the microenvironment. They appear to participate in the physiologic healing process of tissue injury, such as myocardial infarction, by being recruited from the bone marrow, traffic via the circulation and home in to the injured site. Thus such cells may be employed to therapeutically augment the myocardial repair for patients who suffer cardiac damages, which may lead to heart failure. Optimization of the cell implant strategy, and further exploration of the preliminary findings that such adult stem cells may be uniquely immuno-tolerant and thus may be used as universal donors, will further enhance the clinical significance of adult stem cell-based regenerative therapy for heart failure.     

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细胞移植治疗缺血性心肌病是近10年来心血管疾病治疗的热点。随着骨髓干细胞的临床试验数据逐步积累,欧洲心脏病学会年会公布了骨髓干细胞治疗的有效性和安全性,总结其在移植干细胞类型和数量、移植方式和时机、适合人群方面的特点,指出目前的临床研究已经从急性心肌梗死逐步转向心力衰竭患者,并提出了另一种新型诱导多能干细胞的良好远景。     

自体骨髓干细胞移植对心肌梗死患者近期心功能的影响

目的 观察骨髓干细胞（MSCs）移植对合并心力衰竭的急性心肌梗死（AMI）患者近期心功能的影响。方法 将25例AMI患者随机分为MSCs移植组（9例）和对照组（16例）。移植组通过介入法移植MSCs，对照组仅行常规治疗。术后通过心脏超声以及核素显像（SPECT）全面评价心功能。结果 两组患者均健康存活。移植组术后2周起EF及CO显著提高，第6周最明显；SPECT显示心肌梗死面积2周起明显缩小，第6周最明显，第8周与第6周相比无显著差异（P〉0．05）。结论 MSCs移植有望为治疗急性心肌梗死引起的心力衰竭提供一种新思路。     

Adult stem cells in the treatment of acute myocardial infarction

Stem cell therapy has emerged as a novel therapeutic treatment alternative for early and end stage LV dysfunction. The rapid translation into clinical trials has left many questions unanswered. Moreover, results of randomized trials in the setting of acute myocardial infarction are controversial, emphasizing a need for further basic and translational research to improve understanding of cell functionality. This review attempts to summarize some of the functional issues related to cell therapy and also evaluate the current status of stem cell clinical trials. Although results to date have shown modest improvement in left ventricular function, the progress should follow a coordinated, multidisciplinary, and well designed path to address issues of cell homing, cell retention, and also look at outcomes beyond physiological parameters. © 2010 Wiley‐Liss, Inc.     

Hepatocyte cell therapy in liver disease

Liver disease is a leading cause of morbidity and mortality. Liver transplantation remains the only proven treatment for end-stage liver failure but is limited by the availability of donor organs. Hepatocyte cell therapy, either with bioartificial liver devices or hepatocyte transplantation, may help address this by delaying or preventing liver transplantation. Early clinical studies have shown promising results, however in most cases, the benefit has been short lived and so further research into these therapies is required. Alternative sources of hepatocytes, including stem cell-derived hepatocytes, are being investigated as the isolation of primary human hepatocytes is limited by the same shortage of donor organs. This review summarises the current clinical experience of hepatocyte cell therapy together with an overview of possible alternative sources of hepatocytes. Current and future areas for research that might lead towards the realisation of the full potential of hepatocyte cell therapy are discussed.     

Translational research of adult stem cell therapy

Congestive heart failure (CHF) secondary to chronic coronary artery disease is a major cause of morbidity and mortality world-wide. Its prevalence is increasing despite advances in medical and device therapies. Cell based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Functional efficacy of progenitor cells isolated from the bone marrow and the heart have been evaluated in preclinical large animal models. Furthermore, several clinical trials using autologous and allogeneic stem cells and progenitor cells have demonstrated their safety in humans yet their clinical relevance is inconclusive. This review will discuss the clinical therapeutic applications of three specific adult stem cells that have shown particularly promising regenerative effects in preclinical studies, bone marrow derived mesenchymal stem cell, heart derived cardiosphere-derived cell and cardiac stem cell. We will also discuss future therapeutic approaches.     

Combined percutaneous revascularization and cell therapy after failed repair of anomalous origin of left coronary artery from pulmonary artery

This report shows the course of an infant with an abnormal left coronary artery origin arising from the pulmonary artery who underwent failed surgical reimplantation. Treatment entailed combined stent revascularization followed by intracoronary infusion of bone marrow‐derived mononuclear cells. The patient was admitted with an acute coronary syndrome and low cardiac output; he was endotracheally intubated under respiratory assistance. Fourteen months after intracoronary infusion of autologous bone marrow‐derived mononuclear cells, the infant remains symptom‐free with significant recovery of the left ventricular function. These findings suggest that the combination of percutaneous revascularization and cell therapy should be considered in those infants or children in whom salvage therapy for ischemic heart disease is required. © 2009 Wiley‐Liss, Inc.     

骨髓细胞移植对不同程度衰竭心脏功能恢复的研究

目的探讨骨髓干细胞移植(BMT)对哪种程度的心力衰竭更有效。方法结扎小型猪不同部位左前降支血管,造成不同程度心功能(左心室射血分数,LVEF)变化,2周后,将30只造模型成功动物随机分为3组,高LVEF(HLVEF,LVEF≥50%)组,中LVEF(MLVEF,50%>LVEF≥40%)组,低LVEF(LLVEF,LVEF<40%)组,每组分为两个亚组,各组随机经冠状动脉内移植骨髓单个核细胞或磷酸盐缓冲液(PBS),每组各5只动物。结果移植后4周,注射PBS动物LVEF呈进行性下降;而MLVEF+BMT组较移植前增加11.9%(P<0.05),明显高于HLVEF+BMT组和LLVEF+BMT组。冠状动脉造影显示,只有MLVEF+BMT组侧支循环数量较移植前有显著性增加。免疫组织化学显示,注射BMT的3组血管密度明显高于注射PBS的3组,以MLVEF+BMT组最明显。结论经冠状动脉内自体BMT更有利于中度心力衰竭受体心脏功能恢复和血流灌注改善。     

干细胞移植治疗急性心肌梗死是短期有效还是长期有效——国内临床研究现状

干细胞移植在治疗急性心肌梗死方面已经表现出传统治疗方法无可比拟的优越性。文章总结了国内临床研究中干细胞移植疗效的判断,针对干细胞移植技术、干细胞移植类型、移植治疗急性心肌梗死类型等进行分析。国内研究已证实,干细胞移植治疗急性心肌梗死,可以有效地减少心肌梗死缺血面积,减轻左室重构,改善心功能,具有很好的近期疗效和远期疗效。     

骨髓间充质干细胞修复心肌损伤的研究进展

心肌梗死（MI）具有较高的死亡率,大面积MI后幸存的患者,常因心肌结构重构而逐渐发展为心力衰竭,预后往往欠佳。近来研究发现,骨髓间充质干细胞（bone marrow mesenchymal stemcells,BMSCs）作为多潜能干细胞,对受损的心肌具有积极的修复作用,为改善MI患者的预后提供了一个新途径。本文主要就BMSCs修复受损心肌的相关机制作一综述。     

Autologous cell‐based therapy for ischemic heart disease: Clinical evidence,proposed mechanisms of action,and current limitations

Cell‐based therapy is a promising approach for cardiac repair in patients with coronary artery disease. In preclinical and early clinical studies, investigators have preliminary evidence showing that stem cell therapy can safely and effectively improve myocardial perfusion and left ventricular function. Cardiac stem cell therapy may decrease left ventricular remodeling in cases of myocardial infarction and may alleviate symptoms and prevent cardiac enlargement in chronic ischemic heart disease. Various mechanisms, including paracrine effects, are believed to contribute to stem cell‐mediated cardiac repair. Further studies are needed to determine the optimal timing of therapy, best mode of delivery, and most effective cell dose. Cardiac stem cell therapy promises to become an important option for treating patients with coronary artery disease. © 2009 Wiley‐Liss, Inc.     

Cardiovascular and cerebrovascular mortality in patients with preceding asthma exacerbation

See related Editorial     

Improved regional left ventricular function after successful satellite cell grafting in rabbits with myocardial infarction

OBJECTIVE: To evaluate whether satellite cells injected into infarct areas in rabbits remain viable during 6 weeks follow-up and can improve cardiac function as assessed by echocardiography. METHODS: Myocardial infarction was induced in 16 New Zealand white rabbits, by ligation of the marginalis sinistra artery. Tissue from gluteus muscle biopsies was dissected into small pieces and cultured. Within 2-3 weeks the cells were expanded by 2-3 orders of magnitude and were fluorescent labeled. Single cell pellets for resuspension at >10(6)/1 ml were directly injected into the infarct areas in 8 rabbits. In 8 additional rabbits, 1 ml saline was injected (control). Regional left ventricular function was assessed weekly by 2-D echocardiography until animals were sacrificed. Analysis was performed blind and independently by two experienced echocardiographers, based on the American Society of Echocardiography scheme. RESULTS AND DISCUSSION: Six treated and five control rabbits completed the study. One week after the artery occlusion, left ventricular function scoring did not differ between groups, mean 8.7+/-1.6 vs 8.3+/-1.9 (P=0.74). At 6 weeks post-injection, echocardiographic score was significantly better in the treated group, mean 2.6+/-0.9 vs 6.9+/-2.1 (P=0.002). The treated group showed significant gradual segmental improvement between the first week up to week 6. After sacrifice, macro and microscopic transmural areas showed typical changes of myocardial infarction. Histochemical staining identified viable grafted cells in high density 6 weeks post-transplantation in all grafted hearts. CONCLUSION: Autologous satellite cells (skeletal myofiber), can be successfully grafted into rabbit hearts following myocardial infarction and may induce improved regional left ventricular function.     

Immunologic and inflammatory reactions to exogenous stem cells implications for experimental studies and clinical trials for myocardial repair

Intense research is under way to determine the optimal stem cell type and regimen for repairing diseased myocardium. Although initial studies in humans focused on the use of homologous stem cells, allogeneic or xenogeneic stem cells have been studied extensively in experimental work. Clinical trials with allogeneic stem cells are now under way, an approach based on the premise that stem cells and precursor cells are characterized as being immunotolerant. However, evidence indicates that stem cells may gain immune potency in vivo, especially when delivered to inflamed tissue, such as acutely infarcted myocardium. Histopathologic studies show the presence of a lymphohistiocytic inflammatory reaction at the sites of delivery of allogeneic stem cells, a response that is exaggerated with the use of xenogeneic stem cells. The immune-mediated inflammatory reaction to allogeneic and xenogeneic stem cells may elicit a spectrum of effects, ranging from beneficial (e.g., increased paracrine activity) to detrimental (e.g., accelerated damage and removal of stem cells). Although the issue of immune-mediated inflammatory responses to non-self stem cells requires further evaluation, non-self stem cells should not be considered as immunologically inert or exclusively immunosuppressive in vivo.     

Cellular cardiomyoplasty in large myocardial infarction: Can the beneficial effect be enhanced by ACE‐inhibitor therapy?

BACKGROUND: Cellular cardiomyoplasty with bone marrow derived stromal (MSC) and mononuclear (BMNC) cells has been shown to improve performance of infarcted hearts. We performed a comparative study with MSC and BMNC and tested the hypothesis that captopril treatment could enhance the beneficial effect of cell therapy in large myocardial infarctions. METHODS: Male syngeneic Wistar rats underwent experimental infarction and were randomized to receive 1-3 x 10(6) MSC, 10(8) BMNC or vehicle (BSS group). Two additional groups were treated with captopril and received 1-3 x 10(6) MSC (Cap.MSC) or vehicle (Cap). RESULTS: The ejection fraction (EF%) of MSC and BMNC-treated rats was higher than in the BSS rats, eight weeks after transplantation (33.0+/-4.0, 34.0+/-2.0 and 20.0+/-2.0% respectively, P<0.01). Both captopril-treated groups improved EF% similarly. But only captopril plus MSC treatment almost restored cardiac function to control levels, 8 weeks after injection (60.50+/-5.40% vs. 41.00+/-4.50% in Cap.MSC and Cap respectively, P<0.05). Many DAPI-labelled cells were found in the scar tissue of the left ventricle only in the Cap.MSC group. CONCLUSIONS: Cell transplantation with both MSC and BMNC produced a similar stabilisation of heart function, but the success of the cell engraftment and the recovery of cardiac performance were dependent on concomitant treatment with captopril.