Tranylcypromine Causes Neurotoxicity and Represses BHC110/LSD1 in Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids Model.
Tranylcypromine Causes Neurotoxicity and Represses BHC110/LSD1 in Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids Model.
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DOI：
10.3389/fneur.2017.00626
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发表时间：
2017
影响因子：
3.4
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Huang J;Liu F;Tang H;Wu H;Li L;Wu R;Zhao J;Wu Y;Liu Z;Chen J
人类多能干细胞衍生的脑类器官的最新突破为研究不同药物治疗后的人脑和了解人类病理学的复杂遗传背景提供了有价值的平台。在这里，我们鉴定了用于治疗难治性抑郁症的反苯环丙胺，其引起人类诱导的多能干细胞衍生的脑类器官神经毒性，导致增殖活性降低和凋亡诱导。此外，反苯环丙胺治疗影响神经元和星形胶质细胞，这损害细胞密度和排列。最后，组蛋白去甲基化相关基因的染色显示，反苯环丙胺抑制BHC 110/LSD 1靶向基因的转录活性，并增加组蛋白二甲基化K4的表达。这些结果表明，人脑类器官可用作CNS药物筛选的体外模型，以评估药物治疗后正常脑或神经精神疾病患者脑中的结构、细胞和分子变化。
Recent breakthroughs in human pluripotent stem cell-derived cerebral organoids provide a valuable platform for investigating the human brain after different drugs treatments and for understanding the complex genetic background to human pathology. Here, we identified tranylcypromine, which is used to treat refractory depression, caused human-induced pluripotent stem cell-derived brain organoids neurotoxicity, leading to decreased proliferation activity and apoptosis induction. Moreover, tranylcypromine treatment affects neurons and astrocytes, which impairs cell density and arrangement. Finally, staining of histone demethylation-related genes revealed that tranylcypromine suppresses the transcriptional activity of BHC110/LSD1-targeted genes and increases the expression of histone di-methylated K4. These results show that human brain organoids can be applied as an in vitro model for CNS drug screening to evaluate structural, cellular, and molecular changes in the normal brains or brains of patients with neuropsychiatric disorders after drug treatments.
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