Abstract
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.
Highlights
Depression is a common and severe neuropsychiatric disorder of great societal and medical importance, which contributes greatly to world health problem [1]
Recent breakthroughs in human pluripotent stem cells-derived cerebral organoids offer a promising approach for investigating the mystery of human brain [19]
First, made embryoid bodies (EBs) from induced pluripotent stem cell (iPSC) colonies in a six-well plate coated with irradiated MEFs
Summary
Depression is a common and severe neuropsychiatric disorder of great societal and medical importance, which contributes greatly to world health problem [1]. The safety, efficacy, and side effects of different drugs have been extensively studied using current research models [6]. Toxicology, and drug discovery studies, in vitro 3D culture models of the whole organ have been developed for different systems in recent years, such as small intestine. Compared with conventional mice model, this model can recapitulate the human brain development in vitro [20]. The cerebral organoids, which can mimic the endogenous development of human brain, have been applied to different studies as in vitro models for a wide range of brain diseases [16, 21, 22]. 3D human brain organoids show great potential to investigating psychiatric disease origin and pathology, as well as drug screening and genetic modifications [19]
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