Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.

中文翻译：

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移植到小鼠大脑中的人 iPSC 衍生星形胶质细胞会发生形态学变化以响应淀粉样蛋白-β 斑块

越来越多的证据表明星形胶质细胞对导致阿尔茨海默氏病的神经炎症和神经退行性过程有直接贡献，这些证据来自啮齿动物模型的分子和功能研究。然而，这些模型可能无法完全概括人类疾病，因为人类和啮齿动物的星形胶质细胞在形态、功能和基因表达方面存在很大差异。为了应对这些挑战，我们建立了一种方法，通过将人类诱导多能干细胞 (hiPSC) 衍生的星形胶质细胞祖细胞移植到新生儿大脑中来研究小鼠大脑中的人类星形胶质细胞。异种移植的 hiPSC 衍生的星形胶质细胞祖细胞分化为星形胶质细胞，这些星形胶质细胞在小鼠宿主大脑中功能整合，并以细胞自主方式成熟，保留人类特定的形态、独特的特征和生理特性。在阿尔茨海默氏嵌合体大脑中，移植的 hiPSC 衍生的星形胶质细胞对淀粉样蛋白斑块的存在做出反应，这些淀粉样蛋白斑块正在经历似乎独立于 APOE 等位基因背景的形态学变化。总之，我们在这里描述了一种有前途的方法，包括将源自患者的和经过基因改造的星形胶质细胞移植到小鼠大脑中，以研究阿尔茨海默病背景下的人类星形胶质细胞病理生理学。