中国组织工程研究

中国组织工程研究 ›› 2019, Vol. 23 ›› Issue (1): 118-124.doi: 10.3969/j.issn.2095-4344.1532

• 干细胞综述 stem cell review • 上一篇    下一篇

人多能干细胞向多巴胺能神经元分化：异质性的安全风险

陈 丽1，胡 兰1，彭雅南2，杨 柳1，申 辉1，王 埮1，赵振强1   

  1. 1海南医学院第一附属医院神经内科，海南省海口市 570102；2海南医学院神经科学联合实验室，海南省海口市 570100
  • 修回日期:2018-09-07 出版日期:2019-01-08 发布日期:2018-11-28
  • 通讯作者: 赵振强，博士，主任医师，硕士研究生导师，海南医学院第一附属医院神经内科，海南省海口市 570102
  • 作者简介:陈丽，女，1992年生，重庆市人，汉族，海南医学院在读硕士，医师，主要从事干细胞移植与神经系统退行性疾病的研究。
  • 基金资助:

    国家自然科学基金(31260231)，项目负责人：赵振强；海南省重点研发项目(ZDYF2018233)，项目负责人：赵振强；海南省国际合作项目(KJHZ2015-09)，项目负责人：赵振强；海南医学院科研培育基金项目(HY2018-20)，项目负责人：彭雅南；海南省卫生计生行业科研项目(18A200171)，项目负责人：赵振强

Differentiation of human pluripotent stem cells into dopaminergic neurons: security risk for heterogeneity

Chen Li1, Hu Lan1, Peng Yanan2, Yang Liu1, Shen Hui1, Wang Tan1, Zhao Zhenqiang1   

  1. 1Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan Province, China; 2the United Laboratory for Neurosciences, Hainan Medical University, Haikou 570100, Hainan Province, China
  • Revised:2018-09-07 Online:2019-01-08 Published:2018-11-28
  • Contact: Zhao Zhenqiang, MD, Chief physician, Master’s supervisor, the United Laboratory for Neurosciences, Hainan Medical University, Haikou 570102, Hainan Province, China
  • About author:Chen Li, Master candidate, Physician, Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou 570102, Hainan Province, China
  • Supported by:

    the National Natural Science Foundation of China, No. 31260231 (to ZZQ); the Major Research and Development Project of Hainan Province, No. ZDYF2018233 (to ZZQ); Hainan International Cooperation Project, No. KJHZ2015-09 (to ZZQ); Research and Cultivation Project of Hainan Medical University, No. HY2018-20 (to PYN); Research Projects of Hainan Health and Family Planning Industry, No. 18A200171 (to ZZQ)

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摘要：

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文题释义：
多巴胺能神经元：即以合成分泌单胺类神经递质多巴胺为主的神经元，它广泛分布在中枢神经系统，大部分多巴胺神经元位于中脑黑质致密部，少部分分布在视网膜、嗅球、脑室附近和自主神经节。多巴胺能神经元发出神经纤维投射到端脑、间脑、脑干及脊髓，形成投射通路分别控制运动、情感、感知、行为和垂体分泌功能。
人多能干细胞分化过程中的异质性：虽然在过去几年中，人多能干细胞产生诱导性多巴胺能神经元已取得了实质性进展，但产生的仍是多巴胺能神经元和其他非典型的细胞类型的混合物，即现有的分化方案并不十分完美，人多能干细胞源多巴胺能神经分化产物中存在异质性，有进一步优化的必要性。在不断优化的通用方案调控下，分化产物中其他类型细胞主要是丘脑底核的5-羟色胺神经元，主要原因是中脑多巴胺能神经祖细胞既可以产生中脑多巴胺能神经元，又可以产生5-羟色胺神经元，同时中脑多巴胺能神经元不同亚群引起的异质性也尚未引起足够重视。

 

摘要
背景：人多能干细胞源神经细胞移植治疗帕金森病的研究已经取得极大进展，进入了亚临床研究阶段，但依然有许多问题亟待解决，其中一个问题是分化的异质性，这种异质性可以引起移植后宿主体内肿瘤形成、异动症的发生，给患者带来了潜在的、不可预估的安全风险。
目的：总结人多能干细胞分化为多巴胺能神经元的现状、分化方案设计的原理、诱导流程和异质性分化的研究现状，为其移植治疗实现临床转化奠定理论基础。
方法：英文检索词为“iPSC AND Parkinson’s Disease，Induced pluripotent stem cells AND Parkinson’s Disease，ES cells AND Parkinson’s Disease，Embryonic stem cells AND Parkinson’s Disease，Pluripotent stem cells AND Parkinson’s Disease”，中文检索词为“多能干细胞AND帕金森病，诱导多能干细胞AND帕金森病，胚胎干细胞AND帕金森病”，由第一作者检索1980至2018年PubMed 数据库、中文中国知网数据库和万方数据库，查阅近年诱导性多能干细胞源神经元移植治疗帕金森病的相关文献，最终保留46篇文献进行总结。
结果与结论：多能干细胞应用各种不同体外诱导分化方案，可诱导分化为A9多巴胺能神经元，移植后可以促进帕金森病模型动物的行为学及肢体功能的恢复。然而目前的分化方案产物中除了可以分化为A9多巴胺能神经元外，还包括A10多巴胺能神经元、5-羟色胺能神经元等不同的神经元，尚无一种分化方案可以达到均一性分化。优化多能干细胞体外诱导分化条件，同质性分化为A9多巴胺能神经元可以进一步改善帕金森病模型动物的行为学表现，促进该细胞疗法的临床转化。

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
ORCID: 0000-0003-3815-7604(陈丽)

关键词: 帕金森病, 诱导性多能干细胞, 多巴胺能神经元, 细胞分化, 细胞移植, 异质性, 干细胞, 国家自然科学基金

Abstract:

BACKGROUND: The transplantation of human pluripotent stem cell-derived nerve cells for the treatment of Parkinson’s disease has made great progress and the relevant research is at the subclinical stage. However, there are still many problems to be solved. As one of the existing problems, heterogeneity of differentiation can cause tumor formation and dyskinesia in the host after transplantation, which brings potential and unpredictable risks to patients.
OBJECTIVE: To summarize the current status of human pluripotent stem cells differentiated into dopaminergic neurons, the principle and process of differentiation design, the induction process and the research status of heterogeneous differentiation, laying a theoretical foundation for the clinical transformation of transplantation therapy.
METHODS: The keywords were “iPSC AND Parkinson’s disease, induced pluripotent stem cells AND Parkinson’s disease, ES cells AND Parkinson’s disease, embryonic stem cells AND Parkinson’s disease, pluripotent stem cells AND Parkinson’s Disease” in English and Chinese, respectively. Relevant articles published from 1980 to 2018 were retrieved by the first author in the PubMed, CNKI, and WanFang. Literature addressing the treatment of Parkinson’s disease with induced pluripotent stem cell-derived neurons in recent years was reviewed, and finally 46 articles were retained.
RESULTS AND CONCLUSION: A variety of induction differentiation protocols can be used to induce the differentiation of pluripotent stem cells into A9 dopaminergic neurons. Cell transplantation can promote the behavioral and limb function recovery of different Parkinson's disease models. However, in addition to the differentiation of A9 dopaminergic neurons, the current differentiation protocol products include different neurons such as A10 dopaminergic neurons and serotonergic neurons. There is no differentiation scheme that can achieve uniform differentiation. Further optimizing the differentiation conditions of human pluripotent stem cells in vitro and homogenizing differentiation into A9 dopaminergic neurons may further improve the behavioral performance of Parkinson’s disease model animals and promote the clinical transformation of the cell therapy. 

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: Parkinson Disease, Multipotent Stem Cells, Dopamine, Neurons, Tissue Engineering

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