Three-dimensional brain-on-chip model using human iPSC-derived GABAergic neurons and astrocytes: Butyrylcholinesterase post-treatment for acute malathion exposure
Three-dimensional brain-on-chip model using human iPSC-derived GABAergic neurons and astrocytes: Butyrylcholinesterase post-treatment for acute malathion exposure
复制标题
DOI：
10.1371/journal.pone.0230335
复制
发表时间：
2020-03-12
期刊：
影响因子：
3.7
通讯作者：
Yun, Yeoheung
中科院分区：
文献类型：
--
作者：
Liu, Lumei;Koo, Youngmi;Yun, Yeoheung
有机磷酸酯 (OP) 主要通过抑制乙酰胆碱酯酶 (AChE) 活性以及坏死和凋亡来诱导急性和慢性神经毒性。丁酰胆碱酯酶 (BuChE) 是一种外源性 OP 生物清除剂，可用于治疗 OP 暴露。开发可研究 BuChE 急性 OP 暴露后治疗的体外脑模型是先决条件。在这项研究中，我们开发了一个三维（3D）脑芯片平台，其中包含人类诱导多能干细胞（iPSC）衍生的神经元和星形胶质细胞来模拟人类大脑行为。该平台由两个隔室组成：1）嵌入人 iPSC 衍生的 GABA 能神经元和星形胶质细胞的水凝胶，2）具有动态介质流的灌注通道。将脑组织构建体暴露于不同浓度的马拉硫磷 (MT)，然后在 MT 暴露 20 分钟后用 BuChE 处理。结果表明，iPSC 衍生的神经元和星形胶质细胞直接相互作用并在 3D 基质中形成突触，并且 BuChE 处理可提高 MT 暴露至浓度 10(-3) M 后的活力。我们得出结论，具有人 iPSC 衍生脑细胞的 3D 脑芯片平台是研究 OP 暴露的神经毒性和评估 OP 暴露的治疗化合物的合适模型。 治疗。
Organophosphates (OPs) induce acute and chronic neurotoxicity, primarily by inhibiting acetylcholinesterase (AChE) activity as well as by necrosis, and apoptosis. Butyrylcholinesterase (BuChE), an exogenous bioscavenger of OPs, can be used as a treatment for OP exposure. It is prerequisite to develop in vitro brain models that can study BuChE post-treatment for acute OP exposure. In this study, we developed a three-dimensional (3D) brain-on-chip platform with human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes to simulate human brain behavior. The platform consists of two compartments: 1) a hydrogel embedded with human iPSC-derived GABAergic neurons and astrocytes and 2) a perfusion channel with dynamic medium flow. The brain tissue constructs were exposed to Malathion (MT) at various concentrations and then treated with BuChE after 20 minutes of MT exposure. Results show that the iPSC-derived neurons and astrocytes directly interacted and formed synapses in the 3D matrix, and that treatment with BuChE improved viability after MT exposure up to a concentration of 10(-3) M. We conclude that the 3D brain-on-chip platform with human iPSC-derived brain cells is a suitable model to study the neurotoxicity of OP exposure and evaluate therapeutic compounds for treatment.