Lunden Jason W, Durens Madel, Nestor Jonathan, Niescier Robert F, Herold Kevin, Brandenburg Cheryl, Lin Yu-Chih, Blatt Gene J, Nestor Michael W
Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD, USA.
Program in Molecular Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA.
Adv Neurobiol. 2020;25:259-297. doi: 10.1007/978-3-030-45493-7_10.
Autism spectrum condition (ASC) is a complex set of behavioral and neurological responses reflecting a likely interaction between autism susceptibility genes and the environment. Autism represents a spectrum in which heterogeneous genetic backgrounds are expressed with similar heterogeneity in the affected domains of communication, social interaction, and behavior. The impact of gene-environment interactions may also account for differences in underlying neurology and wide variation in observed behaviors. For these reasons, it has been difficult for geneticists and neuroscientists to build adequate systems to model the complex neurobiology causes of autism. In addition, the development of therapeutics for individuals with autism has been painstakingly slow, with most treatment options reduced to repurposed medications developed for other neurological diseases. Adequately developing therapeutics that are sensitive to the genetic and neurobiological diversity of individuals with autism necessitates personalized models of ASC that can capture some common pathways that reflect the neurophysiological and genetic backgrounds of varying individuals. Testing cohorts of individuals with and without autism for these potentially convergent pathways on a scalable platform for therapeutic development requires large numbers of samples from a diverse population. To date, human induced pluripotent stem cells (iPSCs) represent one of the best systems for conducting these types of assays in a clinically relevant and scalable way. The discovery of the four Yamanaka transcription factors (OCT3/4, SOX2, c-Myc, and KLF4) [1] allows for the induction of iPSCs from fibroblasts [2], peripheral blood mononuclear cells (PBMCs, i.e. lymphocytes and monocytes) [3, 4], or dental pulp cells [5] that retain the original genetics of the individual from which they were derived [6], making iPSCs a powerful tool to model neurophysiological conditions. iPSCs are a readily renewable cell type that can be developed on a small scale for boutique-style proof-of-principle phenotypic studies and scaled to an industrial level for drug screening and other high-content assays. This flexibility, along with the ability to represent the true genetic diversity of autism, underscores the importance of using iPSCs to model neurophysiological aspects of ASC.
自闭症谱系障碍（ASC）是一组复杂的行为和神经反应，反映了自闭症易感基因与环境之间可能的相互作用。自闭症代表了一个谱系，其中异质的遗传背景在沟通、社交互动和行为等受影响领域表现出相似的异质性。基因-环境相互作用的影响也可能解释潜在神经学方面的差异以及观察到的行为的广泛变化。由于这些原因，遗传学家和神经科学家很难建立足够的系统来模拟自闭症复杂的神经生物学病因。此外，针对自闭症患者的治疗方法的开发一直极其缓慢，大多数治疗选择都沦为为其他神经疾病开发的 repurposed 药物。充分开发对自闭症患者的遗传和神经生物学多样性敏感的治疗方法需要个性化的 ASC 模型，该模型能够捕捉一些反映不同个体神经生理和遗传背景的共同途径。在一个可扩展的治疗开发平台上，对有自闭症和无自闭症的个体队列进行这些潜在趋同途径的测试需要来自不同人群的大量样本。迄今为止，人类诱导多能干细胞（iPSC）是能够以临床相关且可扩展的方式进行这类检测的最佳系统之一。山中伸弥的四个转录因子（OCT3/4、SOX2、c-Myc 和 KLF4）的发现[1]使得能够从成纤维细胞[2]、外周血单核细胞（PBMC，即淋巴细胞和单核细胞）[3,4]或牙髓细胞[5]诱导生成 iPSC，这些细胞保留了其来源个体的原始遗传学特征[6]，这使得 iPSC 成为模拟神经生理状况的强大工具。iPSC 是一种易于再生且可再生的细胞类型，可以小规模培养用于精品式原理验证表型研究，并扩大到工业规模用于药物筛选和其他高内涵检测。这种灵活性，以及代表自闭症真正遗传多样性的能力，凸显了使用 iPSC 来模拟 ASC 神经生理方面的重要性。
