神经保护
兴奋毒性
神经科学
神经毒性
生物
程序性细胞死亡
诱导多能干细胞
抑制性突触后电位
神经干细胞
谷氨酸受体
胚胎干细胞
细胞凋亡
细胞生物学
干细胞
医学
受体
内科学
生物化学
基因
毒性
作者
Jinyong Xu,Jing Fan,Xueqing Wang,Stephen Eacker,Tae-In Kam,Li Chen,Xiling Yin,Juehua Zhu,Zhikai Chi,Hongzhi Jiang,Rong Chen,Ted M. Dawson,Valina L. Dawson
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2016-04-06
卷期号:8 (333)
被引量:65
标识
DOI:10.1126/scitranslmed.aad0623
摘要
Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.
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