Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Stem Cell Reports. 2024 Aug 13;19(8):1122-1136. doi: 10.1016/j.stemcr.2024.07.002. Epub 2024 Aug 1.
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.
反应性星形胶质细胞在几种神经退行性疾病中被认为对神经元有有害影响，但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，特别是在人类系统中。在这项研究中，我们利用人类多能干细胞（hPSC）模型来研究反应性如何改变星形胶质细胞的功能并介导神经退行性变。将 hPSC 衍生的星形胶质细胞诱导为反应性表型，此时它们表现出肥大的表型和补体 C3 表达增加。功能上，反应性星形胶质细胞显示细胞内钙减少、吞噬能力升高和对血脑屏障的贡献降低。随后，将反应性星形胶质细胞与各种神经元细胞类型共培养可促进形态和功能改变。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、阿尔茨海默病和肌萎缩侧索硬化症），反应性状态加剧了星形胶质细胞疾病相关表型。这些结果表明反应性星形胶质细胞如何调节神经退行性变，这极大地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。
