Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier
Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier
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DOI：
10.1038/s41551-021-00743-8
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发表时间：
2021-06-14
影响因子：
28.1
通讯作者：
Cho, Seung-Woo
中科院分区：
文献类型：
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作者：
Kim, Jin;Lee, Kyung-Tae;Cho, Seung-Woo
具有功能性血脑屏障的神经血管单元芯片概括了引起真菌性脑膜炎的最常见病原体的嗜神经性和屏障穿透性。神经血管单元由星形细胞端足和神经元包围的血管细胞组成，控制脑血流量和血脑屏障（BBB）的通透性，以维持神经元环境的稳态。研究某些病原体和药物如何穿透人血脑屏障并破坏神经元稳态需要体外神经血管单元的微生理模型。在这里，我们展示了隐球菌（引起真菌性脑膜炎的最常见病原体）的嗜神经性及其穿透血脑屏障的能力，可以通过人类神经干细胞、脑微血管内皮细胞和脑血管周细胞在一个由重力驱动的逐步单向流动维持的人类神经血管单元芯片中共同培养来模拟，并概括了血脑屏障的结构和功能特征。我们发现病原体形成细胞簇，穿透血脑屏障而不改变紧密连接，提示胞吞介导的机制。芯片上的神经血管单元可以促进大脑病原体感染机制的研究，以及一系列脑部疾病药物的开发。
A neurovascular-unit-on-a-chip with a functional blood-brain barrier recapitulates the neurotropism and barrier penetration of the most common pathogen causing fungal meningitis.The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood-brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans-the most common pathogen causing fungal meningitis-and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.