Tubular human brain organoids to model microglia-mediated neuroinflammation.
Tubular human brain organoids to model microglia-mediated neuroinflammation.
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DOI：
10.1039/d1lc00030f
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发表时间：
2021-07-13
期刊：
影响因子：
6.1
通讯作者：
Guo F
中科院分区：
文献类型：
--
作者：
Ao Z;Cai H;Wu Z;Song S;Karahan H;Kim B;Lu HC;Kim J;Mackie K;Guo F
人脑类器官，即源自人多能干细胞的 3D 脑组织培养物，在模拟各种神经系统疾病的神经炎症方面具有广阔的潜力。然而，在生成能够概括人脑关键生理特征的标准化人脑类器官方面仍然存在挑战。在这里，我们提出了一种管状类器官芯片装置，可以生成更好的类器官并模拟神经炎症。通过采用 3D 打印的中空网状支架，我们的装置可以轻松地整合到多孔板中，以可靠、可扩展且可重复地生成管状类器官。通过在管状装置通道中引入摇摆流，我们的装置可以灌注营养物质和氧气，以最大限度地减少类器官坏死和缺氧，并将免疫细胞纳入类器官中以模拟神经免疫相互作用。与传统方案相比，我们的方法增加了神经祖细胞增殖并减少了人脑类器官的异质性。作为概念验证应用，我们应用这种方法来模拟暴露于阿片类药物后小胶质细胞介导的神经炎症。我们发现同基因小胶质细胞在接触阿片受体激动剂 (DAMGO) 后被激活，并通过大麻素受体 2 激动剂 (LY2828360) 的进一步治疗转回稳态状态。重要的是，与二维小胶质细胞培养物相比，管状类器官中激活的小胶质细胞具有更强的细胞因子反应。我们的管状类器官装置简单、多功能、价格低廉、易于使用，并且与多孔板兼容，因此可广泛用于常见研究和临床实验室环境。该技术可广泛用于炎症性疾病的基础和转化应用，包括物质使用障碍、神经疾病、自身免疫性疾病和传染病。
Human brain organoids, 3D brain tissue cultures derived from human pluripotent stem cells, hold promising potential in modeling neuroinflammation for a variety of neurological diseases. However, challenges remain in generating standardized human brain organoids that can recapitulate key physiological features of a human brain. Here, we present a tubular organoids-on-a-chip device to generate better organoids and model neuroinflammation. By employing 3D printed hollow mesh scaffolds, our device can be easily incorporated into multiwell-plates for reliable, scalable, and reproducible generation of tubular organoids. By introducing rocking flows through the tubular device channel, our device can perfuse nutrients and oxygen to minimize organoid necrosis and hypoxia, and incorporate immune cells into organoids to model neuro-immune interactions. Compared with conventional protocols, our method increased neural progenitor proliferation and reduced heterogeneity of human brain organoids. As a proof-of-concept application, we applied this method to model the microglia-mediated neuroinflammation after exposure to an opioid. We found isogenic microglia were activated after exposure to an opioid receptor agonist (DAMGO) and transformed back to the homeostatic status with further treatment by a cannabinoid receptor 2 agonist (LY2828360). Importantly, the activated microglia in tubular organoids had a stronger cytokine response compared to those in 2D microglial cultures. Our tubular organoid device is simple, versatile, inexpensive, easy-to-use, and compatible with multiwell-plates, so it can be widely used in common research and clinical laboratory settings. This technology can be broadly used for basic and translational applications in inflammatory diseases including substance use disorders, neural diseases, autoimmune disorders, and infectious diseases.
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影响因子：
46.9
作者：
Lancaster MA;Corsini NS;Wolfinger S;Gustafson EH;Phillips AW;Burkard TR;Otani T;Livesey FJ;Knoblich JA
通讯作者：
Knoblich JA
影响因子：
25
作者：
Galatro, Thais F.;Holtman, Inge R.;Eggen, Bart J. L.
通讯作者：
Eggen, Bart J. L.
影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
通讯作者：
López-Ávalos MD
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.2
作者：
Abud EM;Ramirez RN;Martinez ES;Healy LM;Nguyen CHH;Newman SA;Yeromin AV;Scarfone VM;Marsh SE;Fimbres C;Caraway CA;Fote GM;Madany AM;Agrawal A;Kayed R;Gylys KH;Cahalan MD;Cummings BJ;Antel JP;Mortazavi A;Carson MJ;Poon WW;Blurton-Jones M
通讯作者：
Blurton-Jones M