PDF(Pubmed)
Abstract：
Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer\'s disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.
摘要：
已知反应性星形胶质细胞在几种神经退行性疾病中对神经元产生有害影响。然而，我们对星形胶质细胞如何促进神经毒性的理解仍然不完整，尤其是在人类系统中。在这项研究中,我们利用人多能干细胞(hPSC)模型来研究反应性如何改变星形胶质细胞功能和介导神经变性.hPSC来源的星形胶质细胞被诱导为反应表型，在这一点上，他们表现出肥大的概况和增加的补体C3表达。功能上,反应性星形胶质细胞显示细胞内钙减少，吞噬能力升高，和减少对血脑屏障的贡献。随后，反应性星形胶质细胞与多种神经元细胞类型的共培养促进了形态和功能改变。此外，当在来自患者特异性hPSC的星形胶质细胞中诱导反应性时(青光眼，老年痴呆症,和肌萎缩侧索硬化症），反应状态加剧了星形细胞疾病相关表型.这些结果表明反应性星形胶质细胞如何调节神经变性，大大有助于我们理解反应性星形胶质细胞在神经退行性疾病中的作用。
