Mechanism and application of stem cell transplantation in the treatment of ischemic stroke

doi:10.3969/j.issn.2095-4344.0655

Abstract

Abstract:

BACKGROUND: Once a nerve injury is developed after the onset of ischemic stroke, there is no effective treatment to promote the recovery of nerve function. A large number of experimental studies have proved that stem cell transplantation not only has neuroprotective effects, but also has the potential of cell replacement and functional recovery.
OBJECTIVE: To review the specificity of stem cells, the possible mechanisms of stem cell transplantation for the treatment of ischemic stroke, the viable types of stem cells, the time, location and dose of stem cell transplantation, and the safety of surgery.
METHODS: Using the keywords of “stem cells; transplantation; ischemic stroke” in English and Chinese, respectively, the first author retrieved relevant articles about stem cell transplantation in the treatment of ischemic stroke published from January 2013 to February 2018 in PubMed and CNKI databases. The literature types included clinical research, basic research and review articles. After removal of the articles that were not related to the purpose of the study or repetitive, 55 articles were finally analyzed.
RESULTS AND CONCLUSION: With the development of technology and medicine, more types of stem cells have been discovered. However, due to the problems of cell origin, isolation and purification, and safety, mesenchymal stem cell transplantation for the treatment of ischemic stroke is the most widely used and studied. When selecting the timing, route, and dose of transplantation, 8×10⁵ to 8×10⁶ cells that are transplanted intravenously at 24 to 72 hours after ischemic injury have been widely used in basic or clinical experiments, which provide ideas for future research. However, whether it is the best method requires further experimental verification. Stem cell transplantation has broad application prospects in the treatment of ischemic stroke, and the value of stem cells has been repeatedly confirmed, which undoubtedly provides a new approach for the treatment of cerebral ischemia. However, this treatment method will encounter many challenges and there are still a lot of problems that need to be solved before it is used in clinical practice.

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: Stem Cells, Transplantation, Stroke, Tissue Engineering

CLC Number:

R394.2

Zhang Dong-lin, Li Dan, Wang Min-juan. Mechanism and application of stem cell transplantation in the treatment of ischemic stroke[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(33): 5393-5398.

Figures/Tables 1

2.1 干细胞的特殊性干细胞是一类具有多向分化和自我更新潜能的细胞。在适当的条件下，其可以分化成各种功能细胞，如神经元和少突胶质细胞。这使得干细胞基础及转化医学相关研究成为当前国际上最受关注的领域之一，随着干细胞技术的不断发展，干细胞应用于越来越多疾病的治疗，包括中枢神经系统疾病、心肌损伤、骨关节炎、糖尿病、肝脏疾病、肿瘤等[6]。缺血性脑卒中发病后对于不同种(系)的神经细胞都有影响，这种复杂和广泛的神经元-胶质细胞-内皮细胞相互作用并影响，这就要求用于治疗缺血性脑卒中损伤的移植细胞需要具有干细胞的特性，即分化潜能，可在特定的条件下分化、增殖为成熟的体细胞，如神经细胞、胶质细胞、内皮细胞等。因此，细胞移植只能利用干细胞作为主要的移植细胞治疗缺血性脑卒中。 2.2 干细胞移植治疗缺血性脑卒中可能的机制干细胞移植治疗缺血性脑卒中可能的作用机制：①细胞替代：移植的干细胞进入脑组织结构中，代替损伤的神经元，促进神经传导通路和连接结构的重建；来源于骨髓的骨髓间充质干细胞可分泌碱性成纤维细胞生长因子、胎盘生长因子、血管内皮生长因子等多种细胞因子，可诱导大脑缺血边界区形成新的血管[7-11]；②神经保护和营养：移植的干细胞可分泌神经营养分子、酶、细胞因子等；如脑源性神经营养因子、神经生长因子、胰岛素样生长因子、胶质细胞源性神经营养因子、肝细胞生长因子、表皮生长因子、干细胞因子等，这些因子在脑损伤的保护和促进已损伤神经功能的恢复中起着重要的作用[12-13]。以脑源性神经营养因子为例，脑源性神经营养因子可与其具有高亲和力的酪氨酸激酶受体B蛋白结合启动膜受体酪氨酸蛋白激酶信号传导途径和磷脂酶C信号传导途径等细胞内信号传导途径，发挥促进神经再生和保护作用[14]。在大鼠实验中证实干细胞分泌的神经营养因子可增强神经细胞发生，并减少卒中大鼠模型脑中的小胶质细胞/巨噬细胞浸润，促进卒中后功能恢复[15]。此外，Jablonska等[16]将人脐血衍生神经干细胞移植入缺血性卒中大鼠模型中的研究证实缺血事件可促进内源性神经再生，这可能是通过激活内源性干细胞从而促进内源性神经发生，促进脑损伤区域的内源性神经营养因子表达增加；③炎症和免疫调节：移植的干细胞可以通过抑制炎症局部T淋巴细胞和巨噬细胞的分化阶段发挥免疫调节减轻炎症反应，M1型巨噬细胞或小胶质细胞可分泌破坏性的炎性介导因子，而M2型巨噬细胞或小胶质细胞则能够分泌营养因子对组织起到保护作用，还可以清除损伤的细胞或细胞碎片可促进预后恢复[17-18]。而干细胞可通过分泌因子作用于巨噬细胞，使其由M1型转变为M2型，影响免疫分泌的细胞因子图谱，从而抑制和极化胶质细胞[19-20]。 2.3 可以应用的干细胞类别治疗缺血性脑卒中的干细胞中可分为内源性和外源性2种类型。前者是应用自身的干细胞，包括神经干细胞和造血干细胞。内源性神经干细胞存在于人类和其他哺乳动物中枢神经系统中，主要分布在海马、脉络从和室管膜下区，在缺血缺氧的条件下内源性神经干细胞细胞可发生增殖、迁移，并向神经元细胞和胶质细胞等分化，进而修复中枢神经系统[21-22]，造血干细胞则是通过粒细胞集落刺激因子发挥作用，但由于条件不足且数量有限没有能形成足够的细胞来完全修复缺血损伤区[23-24]。可用于移植的外源性干细胞主要有胚胎干细胞、成体干细胞和诱导多能干细胞[8]。胚胎干细胞具有干细胞所有的特性，具有在适当的环境、条件下转换为任何神经细胞的潜能，是最理想的移植细胞，但是由于其来源存在伦理及法律问题且存在保存及移植后的安全问题[25-26]。虽然胚胎干细胞移植在缺血性脑卒中动物模型研究中表现出理想的效果，但要应用于人类治疗还受到多方面限制[27-28]。外源性成体干细胞包括神经干细胞和间充质干细胞，外源性神经干细胞一般取自胚胎或流产的胎儿，Huang等[29]在动物实验中证实神经干细胞治疗效果显著，但是由于来源受限，不能实现同体移植，且后续存在排斥反应及移植细胞不纯等问题，目前难以应用于临床。间充质干细胞属于成体干细胞中的一大类，其研究最多、使用最广，可来源于人体多处组织、器官中[30]。根据来源不同可分为骨髓间充质干细胞、脐血间充质干细胞、脐带间充质干细胞以及脂肪间充质干细胞等[31]。间充质干细胞的优势在于来源广泛易获取、保存、自体移植不存在免疫排斥反应，且同样具有分化为神经元和神经胶质细胞等的能力。已经开始应用于临床试验，Honmou等[32]应用自体人间充质干细胞进行移植，首次评估了干细胞治疗缺血性脑卒中的可行性与安全性，在其后5年的随访中虽然患者的神经功能恢复的不理想，但并没有发现不良反应。Honmou等[33]在其另一试验中经静脉注射自体骨髓间充质干细胞，对12例缺血性脑损伤患者进行试验，在移植后一周患者的NIHSS评分持续改善，MRI显示梗死体积减小，且无不良反应。诱导多能干细胞最早是由Kazutoshi Takahashi和Shinya Yamanaka报道，由于其可以来源于任何体细胞，所以被认为是过去的十余年中干细胞领域中最令人兴奋的突破之一[34]。诱导多能干细胞与胚胎干细胞功能十分相似，可以分化为机体任何类型的细胞，目前限制诱导多能干细胞应用于临床的唯一问题就是其可形成畸胎瘤，如果这一问题得以解决，那么诱导多能干细胞在细胞移植方面拥有巨大潜力[35-36]。除了上述几种干细胞外，目前在研究的可应用于移植治疗缺血性脑卒中的细胞还包括人畸胎瘤衍生的细胞、源自人类第3磨牙的成人牙髓干细胞、内皮祖细胞等[37-38]。见表1。"

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