The aging of the immune system drives systemic aging and the pathogenesis of age-related diseases. However, a significant knowledge gap remains in understanding immune-driven aging, especially in brain aging, due to the limited current in vitro models of neuro-immune interaction. Here we report the development of a human brain organoid microphysiological analysis platform (MAP) to discover the dynamic process of immune-driven brain aging. We create the organoid MAP by 3D printing that can confine organoid growth and perfuse oxygen and nutrients (and immune cells) to generate standardized human cortical organoids that promote viability, maturation, and commitment to human forebrain identity. Dynamic rocking flow is incorporated for the platform that allows us to perfuse primary monocytes from young (20 to 30-year-old) and aged (>60-year-old) donors and culture human cortical organoids for modeling and analyzing the aged immune cell interacting organoid tissues systematically. We discovered the aged monocytes had increased infiltration and promoted the expression of aging-related markers (e.g., p16 in astrocytes neighboring to monocytes) within human cortical organoids, indicating that aged monocytes may drive brain aging. We believe that our human brain organoid MAP provides promising solutions for basic research and translational applications in aging, neuroimmunological diseases, autoimmune disorders, and cancers.

中文翻译：

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通过人脑类器官微生理分析平台了解免疫驱动的大脑衰老

免疫系统的老化驱动系统性老化和与年龄相关的疾病的发病机制。然而，由于体外研究的有限性，在理解免疫驱动的衰老，尤其是大脑衰老方面，仍然存在重大的知识空白神经免疫相互作用模型。在这里，我们报告了人脑类器官微生理分析平台 (MAP) 的开发，以发现免疫驱动的大脑衰老的动态过程。我们通过 3D 打印创建类器官 MAP，它可以限制类器官的生长并灌注氧气和营养物质（以及免疫细胞），以生成标准化的人类皮质类器官，促进活力、成熟和对人类前脑身份的承诺。该平台结合了动态摇摆流，使我们能够灌注来自年轻（20 至 30 岁）和老年（>60 岁）供体的原代单核细胞，并培养人类皮质类器官以建模和分析老年免疫细胞系统地相互作用的类器官组织。我们发现衰老的单核细胞在人类皮质类器官中的浸润增加并促进了衰老相关标志物（例如，与单核细胞相邻的星形胶质细胞中的 p16）的表达，表明衰老的单核细胞可能会导致大脑衰老。我们相信，我们的人脑类器官 MAP 为衰老、神经免疫疾病、自身免疫性疾病和癌症的基础研究和转化应用提供了有前景的解决方案。