Abstract：
The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration.
摘要：
中枢神经系统（CNS）神经胶质在维持多发性硬化症（MS）的自我自主炎症和驱动临床进展中的作用正在引起科学兴趣。我们应用了基于单一转录因子（SOX10）的方案来加速人类诱导多能干细胞（hiPSC）衍生的神经前体细胞的少突胶质细胞分化，产生自组织的前脑器官。这些类器官包括神经元，星形胶质细胞,少突胶质细胞,和hiPSC衍生的小胶质细胞来实现免疫能力。超过8周,类器官可重复生成的成熟CNS细胞类型，表现出与成人大脑相似的单细胞转录谱。暴露于MS患者的脑脊液（CSF）发炎，类器官适当地模拟了慢性活动性MS中的大胶质细胞-小胶质细胞神经变性表型和细胞间通讯。少突胶质细胞易损性在MS-CSF暴露后第6天出现，减少近50%。时间分辨的类器官数据支持并扩展了可溶性CSF介质在维持导致少突胶质细胞死亡和炎性神经变性的下游事件中的作用。这些发现支持用于药物筛选以停止炎性神经变性的这种类器官模型的实施。
