Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction
Multicellular 3D Neurovascular Unit Model for Assessing Hypoxia and Neuroinflammation Induced Blood-Brain Barrier Dysfunction
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DOI：
10.1038/s41598-020-66487-8
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发表时间：
2020-06-17
影响因子：
4.6
通讯作者：
Atala, Anthony J.
中科院分区：
文献类型：
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作者：
Nzou, Goodwell;Wicks, Robert T.;Atala, Anthony J.
血脑屏障（BBB）是脑血管界面的一个动态组成部分，维持脑内稳态并调节溶质进入脑组织的通透性。邻近内皮细胞之间紧密连接蛋白的表达和外排蛋白的存在阻止了外来物质进入脑实质。然而，血脑屏障功能障碍在许多神经系统疾病中都很明显，包括缺血性中风、创伤和慢性神经退行性疾病。目前，导致血脑屏障功能障碍的主要因素还不清楚。本研究采用多细胞三维神经血管单元类器官，包括人脑微血管内皮细胞、周细胞、星形胶质细胞、小胶质细胞、少突胶质细胞和神经元，模拟缺氧和神经炎症对血脑屏障功能的影响。类器官在0.1% O-2的低氧室中培养24小时。在这种低氧条件下培养的类器官显示出增加的渗透性、促炎细胞因子的产生和增加的氧化应激。抗炎剂，二异松脂醇二糖苷和2-花生四烯醇甘油，在缺氧条件下通过降低类器官中的炎症细胞因子水平显示出保护作用。通过对一种自由基清除剂和一种抗炎内源性大麻素的评估，我们在此报告该模型在候选药物开发中的效用，这些候选药物可能会减少疾病条件下ROS和炎症的影响。这种三维类器官模型概括了缺氧生理条件下和暴露于外源性神经炎症介质时血脑屏障功能障碍的特征，因此可能在疾病建模和治疗开发中具有潜力。
The blood-brain barrier (BBB) is a dynamic component of the brain-vascular interface that maintains brain homeostasis and regulates solute permeability into brain tissue. The expression of tight junction proteins between adjacent endothelial cells and the presence of efflux proteins prevents entry of foreign substances into the brain parenchyma. BBB dysfunction, however, is evident in many neurological disorders including ischemic stroke, trauma, and chronic neurodegenerative diseases. Currently, major contributors to BBB dysfunction are not well understood. Here, we employed a multicellular 3D neurovascular unit organoid containing human brain microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons to model the effects of hypoxia and neuroinflammation on BBB function. Organoids were cultured in hypoxic chamber with 0.1% O-2 for 24hours. Organoids cultured under this hypoxic condition showed increased permeability, pro-inflammatory cytokine production, and increased oxidative stress. The anti-inflammatory agents, secoisolariciresinol diglucoside and 2-arachidonoyl glycerol, demonstrated protection by reducing inflammatory cytokine levels in the organoids under hypoxic conditions. Through the assessment of a free radical scavenger and an anti-inflammatory endocannabinoid, we hereby report the utility of the model in drug development for drug candidates that may reduce the effects of ROS and inflammation under disease conditions. This 3D organoid model recapitulates characteristics of BBB dysfunction under hypoxic physiological conditions and when exposed to exogenous neuroinflammatory mediators and hence may have potential in disease modeling and therapeutic development.