Raabe Florian J, Galinski Sabrina, Papiol Sergi, Falkai Peter G, Schmitt Andrea, Rossner Moritz J
Molecular and Behavioural Neurobiology, Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
NPJ Schizophr. 2018 Nov 19;4(1):23. doi: 10.1038/s41537-018-0066-4.
Postmortem studies in patients with schizophrenia (SCZ) have revealed deficits in myelination, abnormalities in myelin gene expression and altered numbers of oligodendrocytes in the brain. However, gaining mechanistic insight into oligodendrocyte (OL) dysfunction and its contribution to SCZ has been challenging because of technical hurdles. The advent of individual patient-derived human-induced pluripotent stem cells (hiPSCs), combined with the generation of in principle any neuronal and glial cell type, including OLs and oligodendrocyte precursor cells (OPCs), holds great potential for understanding the molecular basis of the aetiopathogenesis of genetically complex psychiatric diseases such as SCZ and could pave the way towards personalized medicine. The development of neuronal and glial co-culture systems now appears to enable the in vitro study of SCZ-relevant neurobiological endophenotypes, including OL dysfunction and myelination, with unprecedented construct validity. Nonetheless, the meaningful stratification of patients before the subsequent functional analyses of patient-derived cell systems still represents an important bottleneck. Here, to improve the predictive power of ex vivo disease modelling we propose using hiPSC technology to focus on representatives of patient subgroups stratified for genomic and/or phenomic features and neurobiological cell systems. Therefore, this review will outline the evidence for the involvement of OPCs/OLs in SCZ in the context of their proposed functions, including myelination and axon support, the implications for hiPSC-based cellular disease modelling and potential strategies for patient selection.
对精神分裂症（SCZ）患者的尸检研究表明，其大脑存在髓鞘形成缺陷、髓鞘基因表达异常以及少突胶质细胞数量改变。然而，由于技术障碍，深入了解少突胶质细胞（OL）功能障碍及其对SCZ的影响一直具有挑战性。个体患者来源的人诱导多能干细胞（hiPSC）的出现，结合原则上任何神经元和神经胶质细胞类型的生成，包括OL和少突胶质细胞前体细胞（OPC），对于理解遗传复杂精神疾病如SCZ的病因发病机制的分子基础具有巨大潜力，并可能为个性化医疗铺平道路。神经元和神经胶质细胞共培养系统的发展现在似乎能够以前所未有的构建效度在体外研究与SCZ相关的神经生物学内表型，包括OL功能障碍和髓鞘形成。尽管如此，在对患者来源的细胞系统进行后续功能分析之前，对患者进行有意义的分层仍然是一个重要的瓶颈。在此，为了提高离体疾病建模的预测能力，我们建议使用hiPSC技术，专注于根据基因组和/或表型特征以及神经生物学细胞系统分层的患者亚组的代表。因此，本综述将概述OPC/OL参与SCZ的证据，及其拟议的功能，包括髓鞘形成和轴突支持，对基于hiPSC的细胞疾病建模的影响以及患者选择的潜在策略。
