2和3维hiPSC衍生和分离的皮质神经元网络中Ca2+振荡的比较评估。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY
John P. Imredy , Gautier Roussignol , Holly Clouse , Giorgia Salvagiotto , Ludmilla Mazelin-Winum
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引用次数: 1

摘要

人类诱导多能干细胞(hiPSC)衍生的神经细胞为模拟神经系统疾病和毒性提供了巨大的潜力,并已在药物发现和毒理学中得到应用。作为欧洲创新药物倡议(IMI2) NeuroDeRisk(临床前药物发现中的神经毒性降低风险)的一部分,我们在这里探讨了2D和3D hiPSC衍生的混合谷氨酸能/ gaba能活性神经元网络的Ca2+振荡反应,其中包括临床和实验确定的癫痫性尿源化合物。这两种类型的网络都是针对Ca2+反应的初级小鼠皮质神经元2D网络模型进行评分,作为建立的比较分析。评估了自发全球网络Ca2+振荡的频率和振幅参数以及药物依赖的方向变化,并使用列联表分析对癫痫的预测性进行了评分。此外,还比较了二维模型之间以及二维模型与三维模型之间的响应。hiPSC神经球体与小鼠原代皮质神经元模型参数反应的一致性最好(频率为77%,振幅为65%)。自发Ca2+振荡频率和振幅的降低被发现是小鼠和神经球体模型之间癫痫性尿原性风险的最基本的共同决定因素,这是基于对具有记录的癫痫性尿原活性的临床化合物的测试。自发Ca2+振荡频率的增加主要是在2D hIPSC模型中观察到的,尽管这种效应对癫痫性尿源性临床化合物的特异性很低(33%),而该模型中尖峰振幅的下降更能预测癫痫性尿源性。模型的总体预测是相似的,由于假阳性率高,检测的敏感性通常超过特异性。与小鼠皮质2D反应相比,hiPSC 3D模型比2D模型的一致性更高,这可能是由于神经球体成熟时间更长(3D成熟84-87天,2D成熟22-24天),以及建立的网络连接的三维性质。自发Ca2+振荡读数的简单性和可重复性支持进一步研究hiPSC衍生的神经元来源及其2和3维网络,用于神经药理学安全性筛选。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Comparative assessment of Ca2+ oscillations in 2- and 3-dimensional hiPSC derived and isolated cortical neuronal networks

Human induced Pluripotent Stem Cell (hiPSC) derived neural cells offer great potential for modelling neurological diseases and toxicities and have found application in drug discovery and toxicology. As part of the European Innovative Medicines Initiative (IMI2) NeuroDeRisk (Neurotoxicity De-Risking in Preclinical Drug Discovery), we here explore the Ca2+ oscillation responses of 2D and 3D hiPSC derived neuronal networks of mixed Glutamatergic/GABAergic activity with a compound set encompassing both clinically as well as experimentally determined seizurogenic compounds. Both types of networks are scored against Ca2+ responses of a primary mouse cortical neuronal 2D network model serving as an established comparator assay. Parameters of frequency and amplitude of spontaneous global network Ca2+ oscillations and the drug-dependent directional changes to these were assessed, and predictivity of seizurogenicity scored using contingency table analysis. In addition, responses between models were compared between both 2D models as well as between 2D and 3D models. Concordance of parameter responses was best between the hiPSC neurospheroid and the mouse primary cortical neuron model (77% for frequency and 65% for amplitude). Decreases in spontaneous Ca2+ oscillation frequency and amplitude were found to be the most basic shared determinants of risk of seizurogenicity between the mouse and the neurospheroid model based on testing of clinical compounds with documented seizurogenic activity. Increases in spontaneous Ca2+ oscillation frequency were primarily observed with the 2D hIPSC model, though the specificity of this effect to seizurogenic clinical compounds was low (33%), while decreases to spike amplitude in this model were more predictive of seizurogenicity. Overall predictivities of the models were similar, with sensitivity of the assays typically exceeding specificity due to high false positive rates. Higher concordance of the hiPSC 3D model over the 2D model when compared to mouse cortical 2D responses may be the result of both a longer maturation time of the neurospheroid (84–87 days for 3D vs. 22–24 days for 2D maturation) as well as the 3-dimensional nature of network connections established. The simplicity and reproducibility of spontaneous Ca2+ oscillation readouts support further investigation of hiPSC derived neuronal sources and their 2- and 3-dimensional networks for neuropharmacological safety screening.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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