Research advances in induced pluripotent stem cells in Alzheimer’s disease

doi:10.3969/j.issn.2095-4344.2017.21.024

Abstract

Abstract:

BACKGROUND: Induced pluripotent stem cell (iPSC) technique is a newborn technology reprogramming human somatic cells into pluripotent stem cells, which can be used in disease modeling, drug screening and cell therapy.
OBJECTIVE: To analyze the feasibility and advances of iPSC application in Alzheimer’s disease, and conclude the insufficient and future of this technology.
METHODS: CNKI and PubMed were searched for relevant articles concerning Alzheimer’s disease and iPSCs, and the retrieval results were screened by relativity and repeatability. Finally, 30 articles were included in result analysis.
RESULTS AND CONCLUSION: This review concludes the superiority of iPSC technology in the treatment of neurodegenerative diseases and in vivo harvest of nerve cells. The use of inducible pluripotent stem cells differentiated from patient's own cells is more practicable, but there are still many problems to solve at this stage, such as high-efficient and stable directional differentiation, safety of induced pluripotent stem cells, the most appropriate donor cells, and ethical disputes.

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: Multipotent Stem Cells, Alzheimer Disease, Tissue Engineering

CLC Number:

R318

Zhu Shi-qi, Li Feng. Research advances in induced pluripotent stem cells in Alzheimer’s disease[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(21): 3426-3431.

Figures/Tables 2

2.1 诱导性多能干细胞技术应用于阿尔茨海默病模型的建立人们对阿尔茨海默病认识的欠缺主要受疾病模型的限制，虽然可以利用转基因小鼠等哺乳动物建立动物疾病模型，但人和小鼠具有种属差异，不能如实地反映人类疾病特点。例如小鼠体内只有表达少量与淀粉样沉淀斑相关的CD11b分子受体的低活性小胶质细胞，而阿尔茨海默病患者体内则具有能表达大量CD11b分子受体的高活性小胶质细胞，所以转基因小鼠脑内无法表现出阿尔茨海默病典型的淀粉样沉淀斑[5]；同时人和小鼠的大脑不论在大小还是在形态结构上都具有明显差异；另外，对于tau转基因小鼠，内源性tau基因在表达过程中会干扰到转入的人tau基因的表达[6]。由于以上差异，人的APP、Presenilin、tau等阿尔茨海默病相关基因在转入后并不能在小鼠体内完整地表达出患者的全部特性。更有利的证据是，曾经在小鼠实验中被证实具有治疗作用的γ-分泌酶无法减轻患者的认知障碍症状[7]，这也进一步证明动物疾病模型并不能很好地适用于阿尔茨海默病的研究。之前人们很难获取阿尔茨海默病患者的活神经元模型，若是利用胚胎干细胞建模则需对另一个生命造成损害，同时涉及一系列伦理学争议。2006年Yamanaka等[2]通过反转录病毒将Oct4、Sox2、c-Myc、KLF4等转录因子导入小鼠皮肤成纤维细胞使其逆分化重编程获得了具有高分化潜能的诱导多能干细胞，由此研究者可以利用阿尔茨海默病患者自身的体细胞重编程来建立患者特异的诱导性多能干细胞系，进一步诱导出具有患者遗传特征的神经外胚层等相关组织以供研究(图1)[8]。Yagi课题组利用PS1 A246E和PS2 N141I突变型家族性阿尔茨海默病(familial AD，FAD)患者的成纤维细胞重编程得到诱导性多能干细胞系，首次成功获得人家族性阿尔茨海默病特异性诱导性多能干细胞系[9]。此后，世界上诸多实验小组成功建立了阿尔茨海默病特异性诱导性多能干细胞疾病模型，其中家族性突变基因有PS1基因的A246E、A79V、H163R、ΔE9、M146L、Y115C突变型；PS2基因的N141I突变型；APP基因的693Δ、K724N、V717I；ApoE3/ ApoE4突变型等(表1)。同时亦有实验室利用散发性阿尔茨海默病(sporadic AD，SAD)患者的体细胞成功重编程出散发性阿尔茨海默病特异性诱导性多能干细胞系[10]。从基因角度讲，家族性阿尔茨海默病具有明显的遗传特性，故建立家族性阿尔茨海默病患者诱导性多能干细胞系的成功率更高。但散发性阿尔茨海默病特异性诱导性多能干细胞疾病模型的成功建立进一步说明了这些散发性阿尔茨海默病患者的发病同样可能是遗传背景所导致，对散发性阿尔茨海默病患者基因组的研究有利于扩充研究者对阿尔茨海默病基因突变型的认识并深入探究该病的发病机制。"

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