细胞模型：亨廷顿舞蹈症患者来源的多能干细胞。

Cellular Models: HD Patient-Derived Pluripotent Stem Cells.

作者信息

Geater Charlene, Hernandez Sarah, Thompson Leslie, Mattis Virginia B

机构信息

Department of Psychiatry and Human Behavior, University of California-Irvine, Irvine, CA, USA.

Sue and Bill Gross Stem Cell Research Center, University of California-Irvine, Irvine, CA, USA.

出版信息

Methods Mol Biol. 2018;1780:41-73. doi: 10.1007/978-1-4939-7825-0_4.

DOI:10.1007/978-1-4939-7825-0_4

PMID:29856014

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded polyglutamine (polyQ)-encoding repeats in the Huntingtin (HTT) gene. Traditionally, HD cellular models consisted of either patient cells not affected by disease or rodent neurons expressing expanded polyQ repeats in HTT. As these models can be limited in their disease manifestation or proper genetic context, respectively, human HD pluripotent stem cells (PSCs) are currently under investigation as a way to model disease in patient-derived neurons and other neural cell types. This chapter reviews embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) models of disease, including published differentiation paradigms for neurons and their associated phenotypes, as well as current challenges to the field such as validation of the PSCs and PSC-derived cells. Highlighted are potential future technical advances to HD PSC modeling, including transdifferentiation, complex in vitro multiorgan/system reconstruction, and personalized medicine. Using a human HD patient model of the central nervous system, hopefully one day researchers can tease out the consequences of mutant HTT (mHTT) expression on specific cell types within the brain in order to identify and test novel therapies for disease.

摘要

亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，由亨廷顿蛋白（HTT）基因中编码多聚谷氨酰胺（polyQ）的重复序列扩增所致。传统上，HD细胞模型包括未受疾病影响的患者细胞或在HTT中表达扩增的polyQ重复序列的啮齿动物神经元。由于这些模型在疾病表现或合适的遗传背景方面可能存在局限性，目前正在研究人类HD多能干细胞（PSC），作为在患者来源的神经元和其他神经细胞类型中模拟疾病的一种方法。本章回顾了疾病的胚胎干细胞（ESC）和诱导多能干细胞（iPSC）模型，包括已发表的神经元分化模式及其相关表型，以及该领域当前面临的挑战，如PSC和PSC衍生细胞的验证。重点介绍了HD PSC建模未来可能的技术进展，包括转分化、复杂的体外多器官/系统重建和个性化医疗。通过使用人类HD患者的中枢神经系统模型，有望有一天研究人员能够梳理出突变型HTT（mHTT）表达对脑内特定细胞类型的影响，以便识别和测试针对该疾病的新疗法。