Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids.
Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids.
复制标题
使用人类诱导多能干细胞衍生的三维脑类器官建模酒精诱导的神经毒性。
DOI：
10.1038/s41398-020-01029-4
复制
发表时间：
2020-10-13
影响因子：
6.8
通讯作者：
Bai X
中科院分区：
文献类型：
--
作者：
Arzua T;Yan Y;Jiang C;Logan S;Allison RL;Wells C;Kumar SN;Schäfer R;Bai X
母亲在怀孕期间接触酒精会对胎儿的发育产生重大影响，导致一系列症状，称为胎儿酒精谱系障碍（FASD），如认知功能障碍和精神障碍，其病理生理学和机制基本上未知。近年来从诱导多能干细胞中分化出的人脑类器官在发育和结构方面与胎儿脑相似。这些模型允许开发比动物模型更相关的体外系统用于研究FASD。使用人类大脑类器官对酗酒进行建模，我们试图量化酒精（乙醇）对类器官内神经病理学表型和信号传导通路的下游毒性作用。结果表明，酒精暴露导致细胞，亚细胞，生物能量代谢和基因表达水平的不健康类器官。酒精诱导类器官凋亡。酒精对类器官的凋亡作用取决于酒精浓度，并在细胞类型之间变化。具体来说，神经元更容易受到酒精诱导的凋亡比星形胶质细胞。乙醇处理的类器官表现出超微结构的变化，如线粒体嵴破坏，线粒体基质强度降低，细胞骨架紊乱。酒精暴露还导致类器官中的线粒体功能障碍和代谢应激，如以下所证明的：（1）与基础呼吸、ATP产生、质子泄漏、最大呼吸和备用呼吸能力相关的线粒体耗氧率降低，以及（2）与对照组相比，酒精处理的类器官中的非线粒体呼吸增加。此外，我们发现酒精处理影响了17，195个基因中199个基因的表达。生物信息学分析显示，这些失调基因与37条与临床相关病理学相关的通路相关，如精神疾病、行为、神经系统发育和功能、有机体损伤和异常以及细胞发育。值得注意的是，这些基因中有187个与神经发育密切相关，和/或与神经系统生理学和神经变性有关。此外，所识别的基因是网络中连接的多个途径的关键调节因子。这项研究首次将狂饮相关FASD的动物模型扩展到人类模型，允许在组织，细胞，亚细胞，代谢和基因水平上深入分析神经毒性。据此，我们提供了新的见解酒精诱导的病理表型，细胞类型特异性的脆弱性，受影响的信号通路和分子网络，可以有助于更好地了解发育神经毒性作用的酗酒在怀孕期间。
Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.
登录
查看更多内容
影响因子：
5.3
作者：
Arai Y;Taverna E
通讯作者：
Taverna E
影响因子：
4.8
作者：
Ayanlaja AA;Xiong Y;Gao Y;Ji G;Tang C;Abdikani Abdullah Z;Gao D
通讯作者：
Gao D
影响因子：
8.8
作者：
Canfield SG;Sepac A;Sedlic F;Muravyeva MY;Bai X;Bosnjak ZJ
通讯作者：
Bosnjak ZJ
影响因子：
3.7
作者：
Co, Marissa;Hickey, Stephanie L.;Konopka, Genevieve
通讯作者：
Konopka, Genevieve
影响因子：
5.7
作者：
Bai X;Yan Y;Canfield S;Muravyeva MY;Kikuchi C;Zaja I;Corbett JA;Bosnjak ZJ
通讯作者：
Bosnjak ZJ