Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells.
Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells.
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DOI：
10.1016/j.mcn.2015.11.010
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Tsai LH
中科院分区：
文献类型：
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作者：
Mungenast AE;Siegert S;Tsai LH
在过去的十年中，诱导多能干细胞（iPS）细胞已经彻底改变了人类体外神经系统疾病模型的效用。iPS衍生和分化的细胞使研究人员能够研究不同细胞类型对健康和疾病的影响，以及在人类遗传背景下进行治疗药物筛选。特别是，阿尔茨海默病（AD）的临床试验经常失败。两个潜在的原因是第一，从啮齿动物模型的最初发现到人类研究的物种差距，第二，不令人满意的患者分层，这意味着由于缺乏表型和遗传标记，根据疾病的严重程度对患者进行亚组。iPS细胞克服了这一障碍，将提高我们对AD疾病亚型的理解。它们允许研究人员对家族性和散发性AD患者的神经细胞进行深入表征，以及对人类细胞进行临床前筛选。在这篇综述中，我们简要概述了iPS细胞在神经系统疾病中的研究现状，沿着这些模型的一般优点和缺陷。我们总结了CRISPR/Cas等基因组编辑技术将如何使研究人员减少人类研究中固有的基因组变异性问题，以及最近与AD相关的iPS细胞研究。然后，我们专注于目前的技术，iPS细胞分化成神经细胞类型，是相关的AD研究。最后，我们讨论了三维细胞培养系统的产生将如何在复杂的细胞环境中理解AD表型的重要性，以及二维和三维iPS细胞模型如何为AD治疗的药物发现和转化研究提供平台。
In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer’s disease (AD) have been often failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD.