New In Vitro Models to Study Amyotrophic Lateral Sclerosis
New In Vitro Models to Study Amyotrophic Lateral Sclerosis
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DOI：
10.1111/bpa.12353
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发表时间：
2016-03-01
期刊：
影响因子：
6.4
通讯作者：
Ferraiuolo, Laura
中科院分区：
文献类型：
--
作者：
Myszczynska, Monika;Ferraiuolo, Laura
肌萎缩性侧索硬化症（ALS）是一种复杂的多因素疾病，其特征在于运动神经元损失，涉及几种其他细胞类型，包括星形胶质细胞、少突胶质细胞和小胶质细胞。在体内和体外模型中的研究已经强调了非神经元细胞对疾病的贡献是主要事件，并且ALS发病机制由细胞自主和非细胞自主机制驱动。过去10年遗传学和体外建模的进步极大地改变了我们研究ALS致病机制的方式。在反式反应DNA结合蛋白基因（TARDBP）的突变，融合在肉瘤（FUS），最近，GGGGCC-六核苷酸重复扩增在9号染色体开放阅读框72（C9 ORF 72）和他们的联系与家族性ALS的鉴定提供了新的途径的调查和假设的病理生理学这种毁灭性的疾病。在同一年，从2007年到现在，神经系统疾病的体外建模技术也经历了令人印象深刻的发展。诱导多能干细胞（iPSC）的出现使ALS领域有机会最终在体外建模，不仅是家族性的，而且是大部分受散发性疾病影响的ALS病例。自2008年以来，当第一个来自患者的人类iPS衍生运动神经元在培养皿中培养时，已经开发了几种不同的技术来通过遗传重编程产生iPSC系，并优化了多种直接转化方法。在这篇综述中，我们将概述人类体外模型迄今为止是如何使用的，自2007年以来它们带来了哪些发现，以及最近的技术进步与遗传发现相结合，极大地拓宽了ALS研究的视野。
Amyotrophic Lateral Sclerosis (ALS) is a complex multifactorial disorder, characterized by motor neuron loss with involvement of several other cell types, including astrocytes, oligodendrocytes and microglia. Studies in vivo and in in vitro models have highlighted that the contribution of non-neuronal cells to the disease is a primary event and ALS pathogenesis is driven by both cell-autonomous and non-cell autonomous mechanisms. The advancements in genetics and in vitro modeling of the past 10 years have dramatically changed the way we investigate the pathogenic mechanisms involved in ALS. The identification of mutations in transactive response DNA-binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC-hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease. In the same years, from 2007 to present, in vitro technologies to model neurological disorders have also undergone impressive developments. The advent of induced pluripotent stem cells (iPSCs) gave the field of ALS the opportunity to finally model in vitro not only familial, but also the larger part of ALS cases affected by sporadic disease. Since 2008, when the first human iPS-derived motor neurons from patients were cultured in a petri dish, several different techniques have been developed to produce iPSC lines through genetic reprogramming and multiple direct conversion methods have been optimised. In this review, we will give an overview of how human in vitro models have been used so far, what discoveries they have led to since 2007, and how the recent advances in technology combined with the genetic discoveries, have tremendously widened the horizon of ALS research.