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在心血管再生间充质干细胞: 新的研究方向和临床应用

马尔钦Majka马切伊·彼得Sulkowski Bogna BadyraMusiałek
HTTPS://doi.org/10.1002/sctm.16-0484

实验和早期临床数据表明,, 由于一些独特的性能, 间充质干细胞 (间充质干) 可以比其它类型的细胞更有效的对难以治疗或治疗的疾病. 由于其易于分离培养以及它们的分泌和免疫调节能力, MSC是在基于细胞的治疗领域中最有前途的选择. 虽然从各种来源的MSCs具有一些共同的特点, 他们还表现出几个重要的区别. 这些变化可能反映, 部分, 龛特定区域的属性从其中细胞起源. 此外, MSC的形态和功能特征易于跨越隔离协议和细胞培养条件的变化. 这些观察表明,制造协议的精心准备,有必要在今后的临床试验中最有效地利用MSC的. 一个典型的人类心肌梗塞涉及大约损失 1 十亿的心肌细胞和2-3十亿其他 (大多内皮) 心肌细胞, 领导 (尽管最大化的药物治疗) 对长度和生活质量的一个显著的负面影响. 尽管有超过十年的深入研究, 寻找“最佳” (安全,最大有效) 细胞类型,以驱动心肌再生继续. 在这篇综述, 我们总结了有关MSC和最新发现的最重要的特征信息的MSCs研究领域, 并描述在心血管再生利用MSC的临床前和早期临床研究的最新数据. 干细胞转化医学 2017;6:1859-1867

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声明的意义
这一简洁的审查讨论的间充质干细胞的现在和未来的应用 (MSC) 在心血管疾病的治疗. 它总结了在这一领域具有很强的重点对MSCs的作用机制进行了临床前和临床试验. 其主要影响在于持续和完成研究的全面总结.

介绍
心血管疾病 (心血管病) 在世界范围内死亡的头号原因 1. 心血管病不仅影响老人也中年人在他们的工作和社会能力的峰值; 于是, 心血管病是社会一个巨大的医疗和经济问题.

近几十年来,在药理学和血管内治疗的巨大进步, 以及在手术技术, 还有今天, 功夫大量被指向心脏疾病的预防 1. 虽然, 心血管病留在患者显著比例的一种慢性进行性负担, 导致心脏衰竭,需要心脏移植或永久左心室支持 1.

在未来的实验性疗法, 人造 (机械) 心脏置换 2 和心肌再生的方法 (包括生物心中) 仍然是最有前途的. 今天, 干细胞再生治疗策略的一大重点.

 

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发现了 1970 [3], 间充质干细胞 (间充质干) 拥有几个特定的​​功能,使其重要的候选人为未来的再生心脏治疗. 今天, 间充质干是由国际社会为细胞治疗定义为自我更新, 该标准培养条件下表现出塑性的粘附性和表达CD73和CD90但不CD45多能细胞, CD34, CD14, 的CD11b, CD79α, CD19, 或HLA-DR表面标记, 在体外多向分化能力 4. 间充质干也被称为间充质干细胞, 多能成祖细胞, 药用信令信元, 和间充质祖细胞 (多用途储值卡); 然而, 的MPC偶尔也列为单元的一个单独的人口 5.

其中MSCs的来源, 骨髓 3 和脂肪组织 6 一直是最常见的研究迄今. 然而, 间充质干在脐带血中也发现 7, 牙髓 8, 滑液 9, 羊水 10, 和尿 11. 脐带沃顿商学院的果冻 (WJ)衍生的MSC最近已经获得显著关注, 由于一些它们的独特性质和它们的用途的可行性的作为可再生细胞的“无限”关闭的,现成的源 12, 13.

虽然从各种来源的MSCs分享几个特点, 他们还表现出一些差异. 在的MSC群体的这些变化可能反映其所源自龛特定区域的属性. 的MSC的功能也易于在细胞培养条件和分离方法的变化 14-16.

从骨髓来源的MSC特性 (的BM-MSC), 脂肪组织 (AT-MSC的) 和WJ (WJ-MSC的) 在不同的培养条件和分化期间变化 15-17. 例如, WJ-MSC的独立表达的细胞培养条件的最高增殖潜能 18, 19. AT-MSC和BM-MSC的, 但不WJ-的MSCs, 在血清的存在下培养产生大量细胞外基质组分. 只有AT-MSC是能够产生胶原蛋白 (一世, II, 和III). 不管细胞培养条件, 的BM-MSC保持高度的促血管生成的功能 15-17. 其他研究表明,骨髓间充质干是最免疫细胞. 这些观测结果表明,干细胞的性质强烈地依赖于细胞来源和培养条件 18, 20, 21 并可能暗示在未来的临床试验中最有效地利用各种的MSCs类型.

本次审查打算提出关于最新发现的简明信息,并在心血管研究领域的临床使用的MSC.

在心血管治疗MSC的角色
直接分化: 不是MSCs的主要机制’ 行动
心脏是填充细胞构建的细胞外基质骨架的泵, 约 30% 这些都是心肌细胞和 70% 这些都是内皮细胞 22. 间充质干具有分化成多种细胞类型的潜力, 包括心肌细胞 23, 24. MSC样细胞可以在血管周围外膜壁龛中找到 25; 此外, 这些细胞可表观遗传学在体外分化成心血管前体 26. 一些学者建议MSC的更广泛的分化潜能在体外,成神经和神经胶质细胞, 骨骼肌细胞, 肝细胞, 和内皮细胞27和体内, 因为新的心肌细胞 28, 血管平滑肌细胞, 和内皮细胞被发现在间充质干注射部位 29. 这些研究和其他研究 30 have shown that MSCs contribute to neovasculogenesis via large and small vessel formation regardless of new muscle generation. Although MSCs are able to differentiate into different cell types, including cardiomyocytes and endothelial cells, this is probably not their primary mechanism of action in cardiovascular regeneration 29.

Cardiac Retention versus Engraftment of MSCs
Effective delivery and enhanced retention of regenerative cells are fundamental to produce a meaningful therapeutic effect 31-35 because if the cells do not reach the target zone in the first place, they have no chance to exert any effect. A further fundamental issue is long‐term engraftment of the therapeutic cells. The latter may be, to some extent, evaluated in animal models 36 but not yet systematically in humans due to technical and safety limitations and label‐specific limitations such as any potential toxic effect on the cell 37 and/or excretion of the label from the therapeutic cell (那是, in most cases, time‐dependent) and may provide a false signal of the cell presence (cell vs. label presence) 38.

Engraftment rate of MSCs appears to be rather low 28. This phenomenon contradicts many preclinical and clinical observations in which robust beneficial effects of MSCs transplantation, such as a decrease in fibrosis, the stimulation of angiogenesis, and the restoration of contractile function, have been observed. Using an improved delivery technique, our group has recently achieved a high and reproducible retention rate (≈30%) of 99Tc‐labeled WJ‐MSCs in the peri‐infarct zone in humans after recent myocardial infarction 39.

Among the key MSCs mechanisms of action, paracrine secretion 40-43 and cell–cell interactions 44-46 appear to be most important. With these mechanisms, repeated administration of the therapeutic cells may be far more relevant to the therapeutic effect than the focus on long‐term engraftment.

Secretion of Diverse Compounds is a Unique Feature of MSCs
MSCs secrete various cytokines, including hematopoietic cell proliferation and differentiation signals such as interleukin‐6, fms‐like tyrosine kinase 3 ligand, a granulocyte and macrophage colony‐stimulating factors 47, 48. They are able to induce cardioprotection via inhibition of cardiomyocyte apoptosis around the area of administration through secretion of anti‐apoptotic and angiogenic factors, such as secreted frizzled‐related protein 2, which modulates the Wnt signaling pathway 41, and vascular endothelial growth factor (VEGF), which stimulates angiogenesis 40. The secretion of proangiogenic molecules is crucial for neovasculogenesis in infarcted hearts, because MSCs lacking VEGF are less effective 40.

重要的, beyond cytokine production, MSCs secrete metalloproteinases that reorganize the extracellular matrix in scar tissue 49. Reverse remodeling of scar tissue and antifibrotic effects in necrotic myocardial tissue are required for the regeneration and functional restoration of infarcted hearts. 此外, MSCs also directly stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) 50, thus contributing to muscle regeneration.

有趣的是, soluble cytokines and remodeling factors are not the only agents secreted by MCSs. Exosomes are small extracellular vesicles that may contain microRNAs and induce biological effects, even at distant locations. MSCs have been shown to secrete exosomes that decrease infarct size in a mouse model of myocardial ischemia/reperfusion injury 43.

Immunomodulation: A Key Attribute of MSC Regenerative Potential
Both innate and adaptive immunity coordinate distinct and mutually nonexclusive events governing cardiac repair. Elimination of the cellular debris, compensatory growth of the remaining cardiac tissue, activation of resident or circulating precursor cells, quantitative and qualitative modifications of the vascular network, formation of a fibrotic scar and the inflammatory response guide the regenerative process following cardiac damage 51.

The most remarkable feature of MSCs is their moderate HLA class I expression and their lack of HLA class II expression, thus resulting in their immunoprivilege 4. In many clinical trials MSCs have been found not to trigger immunologic reactions for as long as 12 months post‐transplantation 52. In contrast, they are known to have immunosuppressive properties, 例如, by promoting monocyte maturation toward anti‐inflammatory type M2 macrophages and producing soluble mediators such as transforming growth factor‐β1, hepatocyte growth factor, prostaglandin E2, indoleamine 2,3‐dioxygenase, heme oxygenase‐1, soluble HLA‐G5, and anti‐inflammatory interleukin 10 [53]. MSCs also arrest B cell and dendritic maturation, downregulate the activating receptors of natural killer cells, suppress proliferation of both T helper cells and cytotoxic T cells, and inhibit T cell production of pro‐inflammatory cytokines 54. Owing to their immunomodulatory properties, MSCs are used to treat graft‐versus‐host disease 55 and may resolve inflammation in infarcted hearts.

Direct MSC Communication with Target Cells
MSCs also interact with other cells directly through cell–cell contacts involving gap junctions 46 and tunneling nanotubes. 例如, MSCs are able to transfer mitochondria through nanotubes 45, thus achieving cardioprotection via respiratory chain salvage in myocytes.

Through direct and indirect communication with cells at injured sites, MSCs recruit other stem cells to facilitate regeneration of injured tissue. One example of such interactions is the SDF‐1α/CXCR4 axis, which regulates homing of hematopoietic stem cells to the injured myocardium 56. 此外, cardiomyocytes can reenter the cell cycle after treatment with some cytokines secreted by MSCs (例如, TGFβ). These observations suggest that MSCs can trigger the repair of injured tissue. These intrinsic features of MSCs make them ideal candidates for regenerative cardiac therapy. 数字 1 sumarizes biological mechanisms of MSCs action.

数字 1
打开如图viewerPowerPoint
Mesenchymal stem cells mechanisms of action in cardiovascular diseases. 缩写: GVHD, graft versus host disease. 资源: Servier Medical Art, modified.

Preclinical Cardiovascular Studies Involving MSCs
Most of the aforementioned cellular mechanisms through which MSCs act in CVDs were originally identified in animal studies. The potential of MSCs to differentiate into cardiomyocytes and engraft into the myocardium has been shown in pioneering experiments in mice 28, which have revealed expression of desmin, β‐myosin heavy chain, α‐actin, cardiac troponin T, and phospholamban, as well as sarcomeric organization of the contractile proteins, in the left ventricles of mice injected with human BM‐MSCs. That and another animal study 57 have shown that the beneficial effects after MSCs injection exceed those attributable to simple differentiation and engraftment of MSCs. Owing to their immunosuppressive properties, MSCs have been found to ameliorate conditions related to non‐ischemic cardiac disorders by resolving inflammation and improving cardiac function via paracrine actions in a rat model of acute myocarditis 58.

The percutaneous injection of allogeneic MSCs into infarcted swine hearts has been found to result in long‐term engraftment, improvement in the ejection fraction, decreased scar tissue formation, and benefits to general cardiac function. 此外, this procedure has been found to be safe and to produce immunoprivilege effects in transplanted cells, because they are not rejected by allogeneic recipients 59. The beneficial effects of MSCs are not restricted to animal models of acute and/or subacute myocardial infarction. Promising results have also been observed in a chronic model of ischemic heart disease in dogs in which MSCs have been found to be able to differentiate into smooth muscle cells and endothelial cells, thus causing increased vascularity and improving cardiac function 60. Autologous MSCs have also been safely delivered into a chronic model of ischemia–reperfusion‐induced cardiomyopathy in pigs, thus resulting in structural and functional reverse remodeling 61.

Large‐animal models such as pigs are best for bridging the gap between basic research and clinical application because their size, anatomy and physiology are similar to those of humans. These models aid in not only selecting the optimal number of transplanted cells and time of transplantation but also establishing the best method (transendocardial vs. intracoronary vs. intravenous) for delivering and imaging transplanted MSCs 62. Although results in preclinical studies are very promising, showing improvement in a wide range of cardiac functions—increased ejection fraction, decrease in scar tissue, reversed remodeling, improved contractility, augmented heart perfusion, and increased blood vessel density 28-30, 40, 43, 53, 58, 61, 63, 64—the long‐term assessment of the safety and efficacy of MSCs is still needed.

Translation of MSC Regenerative Potential into Cardiovascular Clinical Trials
Fundamental considerations in the clinical applications of cellular therapies to stimulate myocardial repair and regeneration are uncompromised safety and maximized clinical efficacy. 一个典型的人类心肌梗塞涉及大约损失 1 十亿的心肌细胞和2-3十亿其他 (大多内皮) 心肌细胞 65, 领导 (尽管最大化的药物治疗) 对长度和生活质量的一个显著的负面影响 1, On a laboratory level, maximization of clinical safety involves evaluation of chromosomal stability 66. Maximization of the cell potential for regenerative capacity involves cell type identification or choice, potential cell pretreatment, and the delivery method to ensure high uptake in the target zone.

Effect of MSCs Transplantation in Acute Myocardial Infarction
In trials focused on the application of MSCs in acute/subacute myocardial infarction, BM‐MSCs have commonly been used (表 1). In one pioneering study, the short‐term (6 个月) safety of intravenous injections of allogeneic MSCs has been analyzed. No arrhythmogenicity or tumorigenicity was observed, and global symptom scores and ejection fractions tended to improve versus the effects in the placebo group 67. 在另一项研究中, BM‐MSCs have been found to be safe for small group of patients with acute myocardial infarction during a 5‐year follow‐up 68.

表 1. Selected clinical trials involving MSCs in cardiovascular disorders
Disorder Trial acronym and/or number Phase Type of trial Cells applied Amount of cells Time from onset Delivery method Results Reference
Myocardial infarction NCT00114452 I randomized, double‐blind, placebo‐controlled, dose escalation alio BM‐MSCs 0.5 × 106/kg, 1.6 × 106/kg, 5.0 × 106/kg 1–10 days intravenous no arrythomogenicity, no tumorogenicity [ 67]
Myocardial infarction NCT00877903 II randomized, double‐blind, placebo‐controlled alio BM‐MSCs undisclosed <7 days intravenous ↓ hypertrophy ↓. arrhythmia, left ventricle reverse remodeling ‐
Myocardial infarction NTR1553 I nonrandomized, controled auto BM‐MSCs >10 × l06 <1 month intramyocardial no adverse effects [ 68]
Myocardial infarction APOLLO, NCT00442806 I/IIa randomized, double‐ blinded, placebo‐ controlled auto AT‐MSCs average 17.4 ± 4.1 × 106 <24 hours intracoronary no adverse effects ↓. scar tissue ↑ perfusion [ 69]
Myocardial infarction ‐ pilot first‐in‐man alio WJ‐MSCs 30 × 106 5–7 days transcoronary no adverse effects [ 13]
Myocardial infarction NCT01291329 II randomized, double‐ blinded, placebo‐ controlled alio WJ‐MSCs 6 × 106 5–7 days intracoronary ↑ ejection fraction ↓ heart perfusion [ 70]
Myocardial infarction CADUCEUS, NCT00893360 I prospective, randomized, controlled auto MSCs+ CSCs 12.5, 25 × 106 1, 5–3 months intracoronary ↓ scar tissue ↑ contractility [ 71]
Chronic ischemic cardiomyopathy POSEIDON, NCTO1087996 I/II randomized comparison, dose escalation alio vs auto BM‐MSCs 20, 100, 200 × 106 not applicable transendocardial ↑ ejection fraction ↓ scar tissue [ 73]
Chronic ischemic cardiomyopathy TAC‐HFT, NCT00768066 I/II randomized, blinded, placebo‐controlled auto BM‐MSCs vs auto BMMNCs 100, 200 × 106 not applicable transendocardial no adverse effects ↓ infarct size [ 74]
Chronic ischemic cardiomyopathy PROMETHEUS, NCT00587990 I/II randomized, blinded, placebo‐controlled auto BM‐MSCs 2 × 107, 2 × 108 not applicable intramyocardial local ↑ contraction ↓ scar tissue [ 75]
Chronic ischemic cardiomyopathy PRECISE, NCT00426868 II randomized, placebo‐ controlled, double‐blinded auto AT‐MSCs 0.4 × 106 / 公斤, 0.8 × 106 / 公斤, 1.2 × 106 /kg not applicable transendocardial ↑ left ventricular mass ↑ contractility ↑ perfusion [ 76]
Chronic ischemic cardiomyopathy C‐CURE, NCT00810238 II/III randomized, single‐blinded, preconditioned auto BM‐MSCs 6–11 × 108 not applicable endoventricular ↑ ejection fraction [ 77]
Ischemic heart failure CHART‐1 NCTO 1768702 III prospective, multicentre, randomized, controlled, double‐blinded auto BM‐MSCs >24 × 106 not applicable endomyocardially with a retention‐ enhanced catheter no adverse effects [ 78]
Chronic ischemic cardiomyopathy, refractory angina MyStromal Cell, NCT01449032 II randomized, double‐ blinded, placebo‐ controlled VEGF‐stimulated alio AT‐MSCs undisclosed not applicable intramyocardial unpublished [ 79]
缩略语: AT-MSC的, MSCs derived from adipose tissue; BMMNCs, bone marrow mononuclear cells; 的BM-MSC, MSCs derived from bone marrow; WJ-MSC的, Wharton’s jelly‐derived MSCs.
In addition to BM‐MSCs, AT‐MSCs have also been tested for efficacy in myocardial regeneration (表 1). In the APOLLO trial, application of AT‐MSCs resulted in improved cardiac function, elevated perfusion, and a decrease in the extent of scar tissue 69. On the basis of the results of this study, an ongoing phase III ADVANCE (NCT01216995) trial was launched. MPCs are also being tested for their safety, feasibility and efficacy in the treatment of acute ST‐elevation myocardial infarction after their intracoronary administration in the AMICI trial (NCT01781390).

WJ is also a promising source of MSCs for clinical application in treating acute myocardial infarction. WJ‐MSCs have been shown to be safe and beneficial in two independent studies 13, 70, and had also positive effects on infarct size and left ventricular contractility 59.

In a study using a different design—CADUCEUS—the application of cardiospheres (mixture of autologous MSCs with CSCs) has been performed. This study has found a moderate decrease in scar tissue and increased viable heart mass and contractility in the treatment group; 然而, there was no change in ejection fraction 71. One‐year follow‐up showed that the safety and therapeutic effects of the intervention were maintained 72.

Efficiency of MSC Transplantation Is Highest in Chronic Ischemic Cardiomyopathy
Chronic ischemic cardiomyopathy is another cardiovascular disorder in which MSCs are being intensively evaluated and are thought to be highly efficient (表 1). In the POSEIDON trial, allogeneic and autologous transendocardial applications of BM‐MSCs have been compared. Both types of cells delivered similar effects—improvement in ejection fraction and a decrease in scar size within 1 year after intervention 73.

In the TAC‐HFT trial, the effects of BM‐MSCs and bone marrow mononuclear cells (BMMNCs) have been compared. Neither cell type triggered serious adverse effects; 然而, 的BM-MSC, but not BMMNCs, caused a decrease in infarct size and improvements in contractility and overall quality of life; 然而, no changes in ejection fraction have been observed 74.

的BM-MSC’ beneficial effects in treating chronic ischemic cardiomyopathy are clear, but the effects tend to be limited and localized to the injection site. In the PROMETHEUS study, patients undergoing coronary artery bypass grafting received autologous MSCs. An 18‐month follow‐up showed improved contraction and perfusion and decreased scar tissue size in injected segments. 然而, the small number of participants and the lack of a placebo group restricts the degree to which these results can be generalized 75.

The effects of MSCs transplantation may be limited not only by the site of injection but also by the number of transplanted cells. Most of the aforementioned trials used dose‐escalation approaches (ranging from 12.5 × 106 至 11 × 108), whereas the ongoing TRIDENT trial—a phase II clinical trial (NCT02013674)—intends to establish the optimal number of transendocardially transplanted allogeneic MSCs, which should at least correspond to the number of cells lost during myocardial infarction while still being a number that is possible to culture and inject.

Bone marrow is not the only source of MSCs that has been tested for treating chronic ischemic cardiomyopathy. AT‐MSCs also yield improvements in total left ventricular mass, heart contractility and perfusion in no‐option patients with chronic ischemic cardiomyopathy, as shown by the PRECISE study 76. An ongoing phase II trial (CONCERT‐CHF) is testing the safety and efficacy of transendocardial injections of autologous MSCs together with c‐kit‐positive CSCs in patients with chronic heart failure.

A slightly different approach involves pretreatment of MSCs with cytokines before transplantation. In the C‐CURE study, MSCs were preconditioned with a cardiogenic cytokine cocktail before application. Increase in the ejection fraction, end‐systolic volume, 6‐minute walking distance and general quality of life were observed, with no systemic toxicity or adverse effects within 2 年份 77. In this approach, MSCs with an increased commitment to a cardiopoietic lineage are believed to be more promising than unstimulated MSCs. The C‐CURE results inspired the multinational CHART‐1 trial, conducted in 39 医院. A recent update from this study has demonstrated the safety of cardiogenic conditioned BM‐MSCs from patients 39 weeks after transplantation 78.

A similar approach has been used in the MyStromalCell study, in which patients received VEGF‐stimulated AT‐MSCs 79. In that study, prior to transplantation, AT‐MSCs were stimulated to differentiate toward an endothelial lineage by culturing for 7 days in VEGF‐A165‐stimulation medium.

有趣的是, there are no current trials making direct comparisons of the effects of MSCs from different sources (例如, AT‐MSCs vs. 的BM-MSC) in the treatment of any cardiac disorder. 同样, no studies have compared cell delivery methods in this manner. This lack of information complicates making assumptions about optimal cell sources or delivery methods.

Studies to date have generally provided optimistic observations concerning the application of MSCs in the treatment of cardiovascular disorders (acute or chronic).

In several models, MSCs have been shown to decrease scar tissue size, increase perfusion and contractility of the injured heart, induce neovasculogenesis and antifibrotic effects in damaged cardiac tissue, and generally improve quality of life. 然而, there is still a need for large, comprehensive, randomized controlled multicenter studies comparing crucial features of MSCs application in CVDs (例如, source and number of cells, culture conditions, 时间, and method of application). Several such studies are in progress, thus warranting cautious optimism with regard to the clinical application MSCs in the near future. 表 1 presents selected clinical trials involving MSCs in cardiovascular disorders.

Enhancing the Efficiency of MSC Therapy: Future Goals
Despite the promising results of clinical studies involving MSCs, constant efforts to enhance MSC performance are being made, primarily because effects observed in preclinical studies are stronger than those in clinical trials. To achieve the best clinical results, optimal conditions for transplantation must be established. These conditions involve duration of the disease (acute or chronic disorder); the dose of cells applied; the overall patient condition, sex and age of the patient; and the age of the cell donor in cases of allogeneic transplants.

The method of cell delivery (intracoronary vs. transendocardial vs. intravenous) is also being debated 37. On the basis of the conclusions of cardiovascular clinical trials, the transendocardial application of 20–100 × 106 MSCs in treating chronic ischemic cardiomyopathy may deliver the best results. 然而, there is a lack of comprehensive studies discussing these issues and showing a reliable efficacy of MSCs transplantation that exceeds the efficacy of standard procedures alone. Ultimately, combined therapies may prove most viable. An interesting concept is to test MSCs as an adjunctive therapy in patients receiving left ventricular assist devices 80.

There is also a lack of data showing the optimal source of MSCs for transplantation. As shown in basic science studies, MSCs can differ across sources in their regenerative potential, 那是, in their level of secreted trophic factors or propensity toward different lineages. 然而, there are many discrepancies among published data regarding the properties of BM‐, AT‐, and WJ‐MSCs. 因此, comprehensive studies are needed to obtain consistent results. Such studies may also improve cell preparation methods for specific clinical trials.

The absence of differences between the effect of autologous and allogeneic BM‐MSCs used in clinical studies for the treatment of ischemic cardiomyopathy has previously been reported 73. 然而, allogeneic cells have advantages over autologous cells in that they can be prepared, expanded and characterized more quickly as off‐the‐shelf‐products that are ready to be applied when needed. Our 13 and another group 70 have suggested the use of an innovative source of allogeneic MSCs, WJ, for treating cardiac disorders. In the CIRCULATE study, WJ‐MSCs will be isolated from umbilical cords and characterized on the basis of their molecular features and their ability to treat cardiac disorders both in in vivo models and in a clinical trial. This approach may address the unmet needs regarding the clinical application of MSCs, which include but are not restricted to the poor availability of abundant autologous cells in the short time period after heart failure. It has been estimated that myocardial infarction is associated with loss of approximately 109 cardiac myocytes 65. 从而, that is the order of magnitude of cells necessary for transplantation within days after a cardiac incident. An off‐the‐shelf approach appears to be more feasible than autologous cell expansion to meet this need.

此外, because cardiovascular disorders mainly affect elderly people with comorbidities (例如, 糖尿病), it is safe to assume that their autologous cells would also suffer “comorbidities,” thereby diminishing the long‐term therapeutic effects of transplanted autologous cells. This risk is overcome via the application of “healthy, young” allogeneic cells.

Sophisticated methods for increasing MSCs efficacy involve (一个) cell transplantation in combination with pharmacotherapy 80; (b) MSCs genetic modification (例如, increasing engraftment potential 81), which may be effective but also hazardous and nonphysiological; (C) MSCs preconditioning (例如, with VEGF, insulin‐like growth factor 1 , bone morphogenetic protein 2 or basic fibroblast growth factor) 64, 79, 82 to induce their differentiation or increase their paracrine properties; and d) application of MSCs on scaffolds 83 or in microcapsules 84 to increase their retention. Future studies are expected to reveal which of these approaches provide the greatest treatment efficacy.

Despite numerous clinical studies showing beneficial effects of MSCs in treating cardiovascular disorders, some authors have called into question the nature of MSCs, and have even suggested that MSCs and fibroblasts cannot be distinguished on the basis of morphology, cell‐surface markers, differentiation potential or immunologic properties 85-87. This highlights the importance of defining MSCs properly and may reflect the trap of inaccurate nomenclature, because no stem‐cell nature would be expected in fibroblasts.

有趣的是, despite of all abovementioned concerns, the level of improvement in left ventricular ejection fraction observed in cell therapy trials is comparable to the levels observed with the use of the most effective pharmacological treatments 39. One common criticism of cellular therapies to stimulate myocardial repair and regeneration involves their seemingly small effect on myocardial contractility, typically evaluated as the left ventricular ejection fraction (LVEF). It needs to be noted that typically reported improvements in LVEF in patients with heart failure by ≈2%–4% 88 are not different from the typical effect of widely recognized pharmacological therapies (例如, beta‐blockers +2.9% 89, angiotensin receptor blockade +1.3% 90, aldosterone inhibition +2.0% 91 or cardiac resynchronization therapy +2.7% 92. It is expected that improvements in cell therapy including the use of unlimited cell sources, reproducible cell harvest, preparation protocols and standardized delivery methods taking advantage of the latest technology will translate into advancing beyond the magnitude of the effect of contemporary pharmacotherapy.

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结论
A number of unique features of MSCs discussed above make them unique and promising therapeutic agents, in the field of stem cell research. Rather than being typical stem cells that differentiate into effector cells, which directly trigger the regeneration of damaged tissues (similar to construction workers at a construction site), they act as governing cells that secrete mediators and/or directly interact with other cells and subsequently stimulate or recruit those cells to perform regenerative actions (similarly to construction site supervisors). To conclusively demonstrate these effects, additional well‐designed randomized multicenter studies are needed before MSCs treatment can become a therapy of choice for the fundamental health problem worldwide, 心血管病. Allogeneic MSCs are particularly interesting as therapeutic agents because they are not only free of fundamental biologic limitations of autologous cells 93 but also can be used as “off‐the‐shelf” therapeutic agents 13.

In a mutual relationship to clinical trials, important issues that need to be addressed at the pre‐clinical and early clinical stage of MSCs applications involve (一个) reduction or elimination of cell antigenicity to reduce or eliminate rejection 54, (b) continued development of improved delivery techniques to enhance myocardial retention and engraftment 62, 和 (C) cell engineering and /or preconditioning 94 to enhance regenerative capacities and enhance survival. Recent study in subacute myocardial infarction in humans indicates an unprecedented high‐grade (systematically 30%–35%) transcoronary施用天然低免疫原性的WJ-MSC的心肌摄取 39. 这超过了≈5倍其它细胞类型的心肌摄取 (如非选择或所选择的骨髓造血或间充质细胞) 95 亚急性人类心肌梗死, 说明一个重要的临床研究方向 96.


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干细胞治疗