Arsenic Impairs Differentiation of Human Induced Pluripotent Stem Cells into Cholinergic Motor Neurons.
Arsenic Impairs Differentiation of Human Induced Pluripotent Stem Cells into Cholinergic Motor Neurons.
复制标题
DOI：
10.3390/toxics11080644
复制
发表时间：
2023-07-25
期刊：
影响因子：
4.6
通讯作者：
Bain LJ
中科院分区：
文献类型：
--
作者：
Perego MC;McMichael BD;McMurry NR;Ventrello SW;Bain LJ
胚胎发育过程中的砷暴露可导致神经发育不良和运动活动的变化。此外，体外研究表明，砷抑制感觉神经元和骨骼肌的分化。在目前的研究中，人类诱导的多能干细胞（iPS）在暴露于高达0.5 μM的砷的情况下，在28天内分化为运动神经元。在第6天，暴露于砷的神经上皮祖细胞（NEP）的神经祖细胞/干细胞标记物巢蛋白（内斯）和神经上皮祖细胞标记物SOX 1的转录水平降低，而这些转录水平在运动神经元祖细胞（MNP）在第12天增加。在第18天的早期运动神经元（MN）中，胆碱乙酰转移酶（CHAT）的表达在暴露于0.5 μM砷的细胞中减少了两倍。RNA测序结果表明，暴露于0.5 μM砷后，胆碱能突触通路受损，参与乙酰胆碱合成（CHAT）、转运（溶质载体，SLC 18 A3和SLC 5A 7）和降解（乙酰胆碱酯酶，ACHE）的基因转录水平在第18天的早期MN中均下调。在第28天成熟的运动神经元，砷显着下调微管相关蛋白2（MAP 2）和ChAT的蛋白表达的2.8倍和2.1倍，分别伴随着减少轴突长度。这些结果表明，暴露于环境相关的砷浓度失调的人iPS细胞分化成运动神经元和损害胆碱能突触通路，表明暴露损害运动神经元的胆碱能功能。
Arsenic exposure during embryogenesis can lead to improper neurodevelopment and changes in locomotor activity. Additionally, in vitro studies have shown that arsenic inhibits the differentiation of sensory neurons and skeletal muscle. In the current study, human-induced pluripotent stem (iPS) cells were differentiated into motor neurons over 28 days, while being exposed to up to 0.5 μM arsenic. On day 6, neuroepithelial progenitor cells (NEPs) exposed to arsenic had reduced transcript levels of the neural progenitor/stem cell marker nestin (NES) and neuroepithelial progenitor marker SOX1, while levels of these transcripts were increased in motor neuron progenitors (MNPs) at day 12. In day 18 early motor neurons (MNs), choline acetyltransferase (CHAT) expression was reduced two-fold in cells exposed to 0.5 μM arsenic. RNA sequencing demonstrated that the cholinergic synapse pathway was impaired following exposure to 0.5 μM arsenic, and that transcript levels of genes involved in acetylcholine synthesis (CHAT), transport (solute carriers, SLC18A3 and SLC5A7) and degradation (acetylcholinesterase, ACHE) were all downregulated in day 18 early MNs. In day 28 mature motor neurons, arsenic significantly downregulated protein expression of microtubule-associated protein 2 (MAP2) and ChAT by 2.8- and 2.1-fold, respectively, concomitantly with a reduction in neurite length. These results show that exposure to environmentally relevant arsenic concentrations dysregulates the differentiation of human iPS cells into motor neurons and impairs the cholinergic synapse pathway, suggesting that exposure impairs cholinergic function in motor neurons.
登录
查看更多内容
影响因子：
4.8
作者：
Choudhary P;Armstrong EJ;Jorgensen CC;Piotrowski M;Barthmes M;Torella R;Johnston SE;Maruyama Y;Janiszewski JS;Storer RI;Skerratt SE;Benn CL
通讯作者：
Benn CL
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
3.9
作者：
Chandravanshi, Lalit P.;Gupta, Richa;Shukla, Rajendra K.
通讯作者：
Shukla, Rajendra K.
DOI：
10.1073/pnas.1734197100
发表时间：
2003-09-30
影响因子：
11.1
作者：
Aubert, J;Stavridis, MP;Smith, A
通讯作者：
Smith, A
影响因子：
3.7
作者：
Chen HL;Yuh CH;Wu KK
通讯作者：
Wu KK