Stem cell therapy for Alzheimer’s disease: research status and developmental trend

doi:10.3969/j.issn.2095-4344.1817

Abstract

Abstract:

BACKGROUND: Alzheimer’s disease is a degenerative brain disease, and there are no known drugs for curing Alzheimer’s disease. Stem cell transplantation provides a new therapeutic method for Alzheimer’s disease.
OBJECTIVE: To reveal the theme, evolutionary path and research progress of stem cell therapy for Alzheimer’s disease, in a bid to provide reference for the research and clinical treatment of Alzheimer’s disease.
METHODS: A computer search of CNKI, CBM, ISI Web of knowledge, and Embace was performed with the keywords of “Alzheimer’s disease” and “stem cells” + “Alzheimer’s disease,” in Chinese and English, respectively. We conducted a visualized knowledge mapping and literature review of stem cell therapy for Alzheimer’s disease using CiteSpace software.
RESULTS AND CONCLUSION: The evolutionary path of research on stem cell therapy for Alzheimer’s disease is closely related to stem cell transplantation research. The main line of this research is single and prominent, which is developed and implemented based on the keywords of “Alzheimer’s disease - stem cells, neural stem cells - transplantation - bone marrow mesenchymal stem cells, mesenchymal stem cells, human umbilical cord mesenchymal stem cells, beta-amyloid - tissue engineering,” and the core domains composed by these keywords. Human stem cell clinical trials are ongoing in the early stage. The safety, efficacy and ethical issues of stem cells should be emphasized. The regulation of stem cell differentiation should become an issue of concern, and individualized stem cell treatment should be implemented as soon as possible.

Key words: Alzheimer’s disease, neural stem cells, bone marrow mesenchymal stem cells, umbilical cord mesenchymal stem cells, CiteSpace, National Natural Science Foundation of China

CLC Number:

Xu Gexin, Zhang Yunxia, Zhang Haiying. Stem cell therapy for Alzheimer’s disease: research status and developmental trend[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(33): 5378-5384.

Figures/Tables 2

图4及表2说明干细胞治疗阿尔茨海默病研究的重要中心节点是“阿尔茨海默病(AD)、干细胞(Stem Cells)、神经干细胞(NSCs)、组织工程、间充质干细胞移植、骨髓”等，主要研究主题词是“阿尔茨海默病、神经干细胞、移植(transplantation)、干细胞、骨髓间充质干细胞(BM-MSCs)、大鼠、β-淀粉样蛋白”等。阿尔茨海默病的发病学说众多，进而出现了多种治疗策略[8-12]。研究发现当前阿尔茨海默病的研究主题可归纳为以下方面：干细胞移植治疗阿尔茨海默病(神经干细胞和胚胎干细胞诱导的神经球移植治疗阿尔茨海默病；骨髓间充质干细胞移植治疗阿尔茨海默病)；干细胞治疗阿尔茨海默病的可能机制[13-14]；促进内源性干细胞分化治疗阿尔茨海默病[15]；外源性干细胞移植治疗阿尔茨海默病(单纯神经干细胞移植和基因工程加工后的神经干细胞移植)[16-17]。Qu等[18]将人神经干细胞移植到大鼠海马，结果表明神经干细胞移植能显著改善衰老大鼠的认知功能。张宇等[19]对间充质干细胞治疗阿尔茨海默病的研究进展进行了综述；袁佳欣等[20]认为人类间充质干细胞向神经细胞方向分化受多种因子调控，干细胞的分化调控是把实验的成果应用于临床治疗的关键环节之一。将图4、表2与阿尔茨海默病研究综述的主题比较发现，当前关于阿尔茨海默病的研究主要由阿尔茨海默病、神经干细胞、移植等关键词构成，主要集中在神经病学与精神病学、临床医学、基础医学等相关领域，但是移植细胞的迁移、移植后如何在损伤部位定向诱导分化、阿尔茨海默病脑内的病理改变如β-样淀粉样沉积、tau蛋白过度磷酸化等是否会抑制外源性神经干细胞的增殖分化，移植方式和时间、移植细胞剂量、位点、是否有安全隐患及疗效等问题均未得到解决。由此可见，对于干细胞治疗阿尔茨海默病的研究尚需进一步加强和深入。 2.3 研究主题的时区图谱分析主题词时区图谱分析可以反映研究主题随时间变化的规律，即研究的演进与脉络[21-23]。应用Citespace的TimeZone View功能，将时间设定为2003至2018年，时间切片为1，每个切片为Top50，N10%，不使用任何网络裁剪，得到干细胞治疗阿尔茨海默病相关主题词后的结果，见图5。图5说明干细胞治疗阿尔茨海默病研究的演进路径与干细胞移植研究密切相关，将干细胞治疗阿尔茨海默病的研究大体可以分成3段进行分析：2003至2008年主要对阿尔茨海默病、神经干细胞、干细胞、移植、大鼠、海马等为主题进行究；说明这个阶段主要是以神经干细胞治疗阿尔茨海默病的理论和实验研究为重点。Zhang等[24]将人胚胎干细胞培养成具有3种分化潜能的神经干细胞，并在新生鼠大脑成功进行了移植和整合、分化实验，发现这些细胞可以分化为3种全部具有神经元、星形胶质细胞、少突胶质细胞分化潜能的细胞。外源性MH P36细胞能在损伤部位替代受损的胆碱能神经元，神经干细胞具有向β-淀粉样蛋白损伤区迁移的趋向性，具有治疗阿尔茨海默病等脑神经退行性病变的功效[25-26]。Kim等[27-29]发现当神经干细胞的迁移性被抑制时，其分化能力同样也被抑制。据此，他认为神经干细胞必须迁移至靶区才能发挥对神经可塑性的影响。Wu等[30]实验进一步说明靶区微环境对神经干细胞的诱导及定向分化具有重要意义。因此，研究如何诱导神经干细胞定向分化为受损区域的功能细胞极为重要。2009至2015年主要围绕骨髓间充质干细胞、干细胞、人脐带间充质干细胞、β-淀粉样蛋白、神经元等关键词构成。2016至2018年主要由组织工程、细胞凋亡、细胞移植等核心关键词构成，但该阶段的突破性进展和创新性应用尚有待加强。为进一步使从关键词聚类和时区图做出的对阿尔茨海默病的研究更加科学和严谨，下面结合文献来对阿尔茨海默病的研究进行理论脉络归纳。"

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