患者 iPSC 模型揭示了多发性硬化症的神经胶质内表型。

Cell stem cell Pub Date : 2024-11-07 Epub Date: 2024-08-26 DOI:10.1016/j.stem.2024.08.002
Benjamin L L Clayton, Lilianne Barbar, Maria Sapar, Kriti Kalpana, Chandrika Rao, Bianca Migliori, Tomasz Rusielewicz, Daniel Paull, Katie Brenner, Dorota Moroziewicz, Ilana Katz Sand, Patrizia Casaccia, Paul J Tesar, Valentina Fossati
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引用次数: 0

摘要

多发性硬化症(MS)是中枢神经系统(CNS)的一种炎症和神经退行性疾病,会导致神经系统残疾,并随着时间的推移而恶化。虽然在确定免疫系统在多发性硬化症病理生理学中的作用方面取得了进展,但中枢神经系统内在细胞功能障碍的作用仍不清楚。在这里,我们从不同临床亚型的多发性硬化症患者身上收集了一系列诱导多能干细胞(iPSC),并将它们分化成胶质丰富的培养物。利用单细胞转录组分析和正交分析,我们观察到多发性硬化症培养物的几个显著特征,这些特征指向胶质细胞内在疾病机制。我们发现,原发性进行性多发性硬化症衍生培养物含有较少的少突胶质细胞。此外,多发性硬化症衍生的少突胶质细胞系细胞和星形胶质细胞显示免疫和炎症基因表达增加,与多发性硬化症死后大脑胶质细胞的表达相匹配。因此,iPSC衍生的多发性硬化症模型提供了一个独特的平台,可用于剖析神经胶质对疾病表型的贡献,而不受外周免疫系统的影响,并确定潜在的神经胶质特异性治疗干预靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis.

Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system's role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear. Here, we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.

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