Mesenchymal stem cells in the treatment of myocardial infarction: how long is the way from bench to bedside?

doi:10.3969/j.issn.2095-4344.2017.17.023

Abstract

Abstract:

BACKGROUND: Mesenchymal stem cells, a kind of popular seed cells for cell transplantation after myocardial injury, have become a hot research topic in the treatment of ischemic heart diseases.
OBJECTIVE: To review the new progress of mesenchymal stem cell transplantation in the treatment of ischemic heart diseases.
METHODS: We searched Medline, Ovid Embase, PubMed Central, Cochrane Library, Chinese Periodical Full-Text Database, Chinese Biomedical Literature Database, VIP database, Wanfang Database for relevant articles in Chinese and English languages, and the retrieval time was from 1985 to 2015. Articles related to randomized controlled trials or clinical research on mesechymal stem cell transplantation for treatment of ischemic heart diseases were included, and relevant review were also included. Observational studies, case reports, study protocols with no standard or rational design, reviews with no normative and rigorous inclusion criteria, cross-test studies, cluster randomized trials, and studies that have nothing to do with the topic were excluded.
RESULTS AND CONCLUSION: Through literature screening, we summarize the research progress in the mesenchymal stem cell transplantation, including cell source, safety, efficacy, action of mechanism and injection mode, and analyze the merits and demerits of mesenchymal stem cell transplantation. Bone marrow mesenchymal stem cell transplantation provides a new insight into the clinical treatment of myocardial infarction, but there are still many problems to be solved, such as cell quality, cell dose, transplantation mode, transplantation timing and patient selection, which so limit the clinical application of mesenchymal stem cell transplantation.

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

Key words: Myocardial Infarction, Mesenchymal Stem Cell Transplantation, Tissue Engineering

CLC Number:

R318

Zhao Qi-ming, Sheng Kai, Zhang Xuan-fen. Mesenchymal stem cells in the treatment of myocardial infarction: how long is the way from bench to bedside?[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(17): 2766-2775.

Figures/Tables 2

2.1.2 脐血[16-17] 脐血间充质干细胞介于成体干细胞、胚胎干细胞之间，显得更为原始，具有亚全能分化潜能，能分化为心脏、肝、肾等重要器官组织细胞。2000年，Erices等报道脐血中有很丰富的造血干细胞和间充质干细胞，提取出的干细胞也被多位研究者们证实具有良好的心肌修复功能。Lee等[18]发现从脐血中提取的间充质干细胞可分化为中胚层细胞，推测心肌作为中胚层组织亦可由其分化得到。另外有研究发现向兔心肌梗死模型中联合移植脐血间充质干细胞和脐血CD34+，可明显降低胶原蛋白沉积，并提高心肌功能[19]。并由于全球人类出生率高，脐血也能够通过脐血库很好的收集与保存，脐血间充质干细胞已被越来越多的研究者们重视，但因需在孕期采脐血，脐血间充质干细胞的提取仍存在争议[20]。 2.1.3 脐带脐带组织，包括其动脉、静脉、华氏胶组织(Wharton’s jelly)、脐带内膜等，是间充质干细胞的可靠来源。脐带间充质干细胞具有获得过程无需有创操作，可分化为3个胚层细胞、易在组织受损或炎症反应部位聚集、可促进组织修复并调节炎症反应等明显优势[21]。另外，与骨髓间充质干细胞相比，脐带间充质干细胞自我更新快且不易形成畸胎瘤[22]。来源于Wharton’s jelly的间充质干细胞因其对心肌组织具有特异性趋化以及可分泌血管生成因子诱导心肌干细胞募集而受到关注[23-24]。Wharton’s jelly间充质干细胞从胚胎外胚层组织中提取，已被证实具有人胚胎干细胞和成体干细胞的特性，因而可作为干细胞移植的来源，另外，它还被证实具有阻隔免疫排斥、肿瘤发生、畸胎瘤形成等作用[23，25]。经冠状动脉注射Wharton’s jelly间充质干细胞，可明显提高左室射血分数，减少心肌梗死相关事件的发生，因而有望替代骨髓间充质干细胞[26]。 2.1.4 其他大隐静脉、滑膜是近几年发现的较有潜力的间充质干细胞来源组织[27-28]。 2.2 间充质干细胞的安全性和有效性 Fazel等[29]认为间充质干细胞体外扩增的过程是安全的，且癌变的概率很小。但Furlani等[30]认为间充质干细胞长期在体外扩增过程中会产生异常的细胞群落，不但没有治疗心肌梗死的疗效，甚至会发生癌变。更有趣的是，Khan等[31]于2011年的实验中发现间充质干细胞的供体年龄会影响移植后的疗效。实验中，Khan等分别从2月龄和18月龄大鼠中提取出间充质干细胞移植入18月龄心肌梗死模型大鼠体内。移植后观察大鼠体内衰老主导基因p16的表达，发现来自年老大鼠的间充质干细胞表达更加活跃，并由此推断间充质干细胞的活跃程度并不随年龄的增长而降低。除此之外，胰岛素样生长因子1、纤维母细胞生长因子、血管内皮生长因子、肝细胞生长因子较年轻大鼠减少，而各项心功能指标也有所不及。这项研究结果表明了间充质干细胞移植需要年轻的供体，而临床上治疗年老者心肌梗死时自体间充质干细胞移植可能并不适用。 2.3 作用机制 2.3.1 间充质干细胞分化成心肌细胞通过实验发现，小鼠间充质干细胞在体外经过5-氮胞苷处理后，能诱导分化出自发跳动、具有心肌细胞形态和电机械特征的细胞[9，32]。研究进一步证明了骨髓间充质干细胞可以在体内心脏局部微环境中诱导分化生成心肌细胞[33-34]。胰岛素样生长因子1、干细胞生长因子、骨形态发生蛋白2等细胞因子通过与其受体结合，激活PI3-K/Akt信号转导途径，从而介导干细胞在移植微环境中的存活[35]。 2.3.2 旁分泌以往研究者认为干细胞移植改善肌细胞的作用是由干细胞分化替代原损伤的心肌细胞或者血管生成来完成[36-37]，但越来越多的研究证明干细胞可通过旁分泌来促进心肌细胞的自身修复[38-42]。 Ma等[43]于2009年尝试使用分化功能被抑制的间充质干细胞进行移植实验，发现其也能改善实验动物的心脏功能，且其改善程度与分化功能未被抑制的间充质干细胞无统计学差异。同年，Deuse等[44]做了有关间充质干细胞移植治疗鼠心肌梗死的动物实验，证明了生长因子等对间充质干细胞移植疗效的积极作用。这一结果证实细胞因子对心肌修复的作用大于心肌再生。随后的研究中，研究者通过基因重组技术培养出高表达肝细胞生长因子和血管内皮生长因子的间充质干细胞，不管是体外研究还是体内研究，均明显增加了间充质干细胞的增殖。移植了高表达肝细胞生长因子和血管内皮生长因子的间充质干细胞的动物心肌梗死面积更小，梗死区周围血管密度更高，左室功能更好。更详细的分析发现动物心肌组织乳酸脱氢酶分泌减少，心肌细胞凋亡减少，而Akt的活性增加。Gnecchi等[45]在随后的实验中阐述了Akt通路在心肌修复中的具体机制。动物实验中，Akt通路激活程度增加的大鼠心肌细胞摄入2-去氧葡萄糖(2-DG)明显减少，胞浆的pH值也在正常范围内。2-DG是天然的抗代谢类抗生素，能够抑制细胞生长。故此推测Akt通路激活能够保护细胞正常的能量代谢，维持正常的胞内pH值。除此以外，大量的实验也已证实干细胞分泌的其他生长因子(如血小板源性生长因子、上皮生长因子等)能够促进心肌修复，分泌的白细胞介素6、白细胞介素10、肿瘤坏死因子α等细胞因子能够调节免疫炎症反应，可激活细胞内包括STAT3、PI3K-Akt、ERK1/2等在内的信号通路，促进细胞增殖[46]，分泌胶原蛋白Ⅰ、Ⅲ等改善心脏收缩功能。还有研究认为，骨髓间充质干细胞可以通过诱导心脏成纤维细胞转化为肌纤维母细胞，再通过旁分泌作用修复梗死心肌[47]，但Bader等[48]的体外实验发现成纤维母细胞对缺血心肌的保护作用却不及间充质干细胞好。而Li等[49]将间充质干细胞与心肌细胞共培养2周后得到经预处理分化的骨髓间充质干细胞。随后的动物实验发现预处理分化的骨髓间充质干细胞在恢复心功能方面比间充质干细胞更加有效，推测也是利用旁分泌的作用促进了间充质干细胞移植后的疗效。 2.3.3 介导免疫反应间充质干细胞具有强大的免疫调节作用，将成为心肌梗死后平衡炎症反应和达到心肌修复的重要手段。Ben-Mordechai等[50]发现间充质干细胞对损伤心肌的保护作用是巨噬细胞介导的。间充质干细胞对T细胞的调节：心肌梗死发生后，T细胞识别特异性抗原内源性心肌肌球蛋白和辅肌动蛋白，导致辅助T细胞(Th细胞)和细胞毒T细胞(Tc细胞)对心肌产生持续性损害[51]。间充质干细胞与T细胞共培养下有2条主要通路抑制T细胞增殖：间充质干细胞上调色氨酸的代谢酶IDO使色氨酸代谢产物犬尿氨酸堆积，抑制T细胞增殖[52]；环氧合酶2的表达使PGE2释放增加也产生对T细胞增殖抑制的作用[53]。间充质干细胞对B细胞的调节：间充质干细胞有抑制NK细胞增殖的能力，同时也能降低其细胞毒性和减少促炎因子的释放[54]。NK细胞是通过IDO途径和PGE2途径迅速降低其增殖能力，且这两条途径还可能存在协同作用[55]。间充质干细胞也可通过下调NK细胞活化受体NKp30、NKp44 和NKG2D，从而减少NK细胞的活化，使其细胞毒性降低和促炎因子释放减少[56]。间充质干细胞对树突细胞的调节：树突细胞是体内最重要的抗原递呈细胞，心肌梗死后递呈坏死心肌组织，从而激活免疫应答。间充质干细胞可以通过阻断树突细胞的成熟，导致树突细胞表面抗原表达和共刺激分子CD40、CD80和CD86的表达下调，从而抑制T细胞的激活[55]。 2.3.4 其他此外，有研究表明，间充质干细胞能够促进损伤血管的再内皮化，减轻新生内膜的增殖，有助于减轻损伤血管的再狭窄[57]。间充质干细胞治疗缺血性心脏病的作用机制见表1。"

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