Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease.
Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease.
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完全确定阿尔茨海默病患者的人类多能干细胞来源的小胶质细胞和三培养系统模型C3的产生。
DOI：
10.1038/s41593-020-00796-z
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发表时间：
2021-03
影响因子：
25
通讯作者：
Studer L
中科院分区：
文献类型：
--
作者：
Guttikonda SR;Sikkema L;Tchieu J;Saurat N;Walsh RM;Harschnitz O;Ciceri G;Sneeboer M;Mazutis L;Setty M;Zumbo P;Betel D;de Witte LD;Pe'er D;Studer L
中枢神经系统(CNS)的异常炎症被认为是人类神经退行性疾病的主要致病因素。我们开发了一种新的从人多能干细胞(HPSC)中分离小胶质细胞的方法，并建立了一个明确的hPSC来源的三培养系统，该系统包含了hPSC来源的小胶质细胞、星形胶质细胞和神经元的纯群体，以在体外沿着神经炎性轴解剖细胞串扰。我们使用三培养系统来模拟阿尔茨海默病的神经炎症，并用携带APPswe+/+突变的hPSCs及其同基因对照。我们发现补体C3是一种在炎症条件下增加并与突触丢失有关的蛋白质，在三次培养中增强，在APPswe+/+三次培养中进一步增强，这是因为小胶质细胞启动与星形胶质细胞的相互信号以产生多余的C3。我们的研究确定了导致AD患者C3增加的主要细胞因子，并提供了一个广泛适用的平台来研究人类疾病中的神经炎症。
Aberrant inflammation in the central nervous system (CNS) has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a novel approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular crosstalk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer’s Disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in AD and presents a broadly applicable platform to study neuroinflammation in human disease.
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