Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.
Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.
复制标题
DOI：
10.1016/j.brainres.2015.09.023
复制
发表时间：
2016-05-01
期刊：
影响因子：
2.9
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Liu Y;Deng W
通过引入特定的转录因子对体细胞进行重编程，从而生成具有与胚胎干细胞（ESC）相当的多能性的“诱导多能干细胞（iPSC）”，利用该技术可以生产从活体中难以获得的各种细胞和组织。这一进展正在为基于 iPSC 的疾病建模、药物筛选和再生医学带来快速进展。越来越多的研究表明，成人发病的神经退行性疾病的表型可以在 iPSC 衍生的神经细胞培养物中相当忠实地重现。此外，尽管这些疾病具有成人发病的性质，但致病表型和细胞异常通常存在于早期发育阶段，这为了解神经退行性疾病的潜在机制和发现新药物提供了新的“机会之窗”。细胞重编程技术可以采用逆向工程方法来模拟多种人类疾病的细胞退行性表型。一个很好的例子是使用 iPSC 对人类神经退行性疾病肌萎缩侧索硬化症 (ALS) 进行的研究。 ALS 是一种进行性神经退行性疾病，其特征是上运动神经元和下运动神经元 (MN) 丧失，最终导致肌肉萎缩并因呼吸衰竭而死亡。 iPSC 方法提供了创新的细胞培养平台，作为 ALS 患者衍生的模型系统。研究人员将来自 ALS 患者的 iPSC 转化为 MN 和各种类型的神经胶质细胞（所有这些细胞都与 ALS 相关），以研究这种疾病。 iPSC 技术可用于确定特定遗传因素的作用，以追踪“培养皿中的疾病”模型中神经退行性疾病过程中的问题。同时，还可以进行针对人类 ESC 中相同特定基因的平行实验，以控制和补充基于 iPSC 的 ALS 疾病建模研究方法。对 ALS iPSC 和 ESC 的研究已经产生了很多知识。由于这些方法各有优缺点，应在实验设计中权衡利弊，以便相互补充，因此结合不同的方法将有助于扩大 ALS 病理生理学的知识。目标是利用ESC和iPSC对人类疾病进行逆向工程，生成谱系报告系和体外疾病模型，靶向疾病相关基因，以便更好地理解沿神经（神经元与神经胶质）谱系分化调节的分子和细胞机制，揭示神经退行性疾病的发病机制，并为替代治疗提供合适的细胞来源。
With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of “induced pluripotent stem cells (iPSCs)” with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new “windows of opportunity” for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what’s wrong in the neurodegenerative disease process in the “disease-in-a-dish” model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control and to complement the iPSC-based approach for ALS disease modeling studies. Much knowledge has been generated from the study of both ALS iPSCs and ESCs. As these methods have advantages and disadvantages that should be balanced on experimental design in order for them to complement one another, combining the diverse methods would help build an expanded knowledge of ALS pathophysiology. The goals are to reverse engineer the human disease using ESCs and iPSCs, generate lineage reporter lines and in vitro disease models, target disease related genes, in order to better understand the molecular and cellular mechanisms of differentiation regulation along neural (neuronal versus glial) lineages, to unravel the pathogenesis of the neurodegenerative disease, and to provide appropriate cell sources for replacement therapy.