Cruceanu Cristiana, Dony Leander, Krontira Anthi C, Fischer David S, Roeh Simone, Di Giaimo Rossella, Kyrousi Christina, Kaspar Lea, Arloth Janine, Czamara Darina, Gerstner Nathalie, Martinelli Silvia, Wehner Stefanie, Breen Michael S, Koedel Maik, Sauer Susann, Sportelli Vincenza, Rex-Haffner Monika, Cappello Silvia, Theis Fabian J, Binder Elisabeth B
Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany (Cruceanu, Dony, Krontira, Roeh, Kaspar, Arloth, Czamara, Gerstner, Martinelli, Wehner, Koedel, Sauer, Sportelli, Rex-Haffner, Binder);International Max Planck Research School for Translational Psychiatry, Max Planck Institute of Psychiatry, Munich (Dony, Krontira, Kaspar, Gerstner);Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany (Dony, Fischer, Arloth, Theis);TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany (Fischer);Max Planck Institute of Psychiatry, Munich (Di Giaimo, Kyrousi, Cappello);Department of Biology, University of Naples Federico II, Naples, Italy (Di Giaimo);First Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, and University Mental Health, Neurosciences, and Precision Medicine Research Institute "Costas Stefanis," Athens, Greece (Kyrousi);Department of Psychiatry, Department of Genetics and Genomic Sciences, Seaver Autism Center for Research and Treatment, and Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York (Breen);School of Life Sciences Weihenstephan and Department of Mathematics, Technical University of Munich, Munich (Theis);Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (Binder).
Am J Psychiatry. 2022 May;179(5):375-387. doi: 10.1176/appi.ajp.2021.21010095. Epub 2021 Oct 26.
A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain.
The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development.
The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors.
These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.
糖皮质激素受体（GR）激活的精细平衡对于器官形成至关重要，其紊乱会影响许多健康结局。在子宫内，糖皮质激素与脑相关的负面结局有关，但其潜在机制尚不清楚，尤其是关于细胞类型特异性效应。利用人诱导多能干细胞（hiPSC）衍生的脑类器官这一胎儿人类脑发育的体外模型，来测试脑类器官是否适合研究产前糖皮质激素暴露对发育中大脑的影响。
用合成糖皮质激素地塞米松激活GR，并通过单细胞转录组学描绘发育过程中的效应。
GR在所有细胞类型中均有表达，且随着发育表达水平升高。其激活不仅引发向细胞核的转位以及对已知GR调节途径的预期效应，而且神经元和祖细胞还显示出对分化和成熟相关转录本的靶向调节。在神经元中独特的是，差异表达的转录本在与行为相关表型和疾病相关的基因中显著富集。这种人类神经元糖皮质激素反应谱在来自三个独立hiPSC系的脑类器官中得到验证，这些hiPSC系由来自男性和女性供体的不同来源组织重编程而来。
这些发现表明，糖皮质激素暴露过多可能会干扰子宫内神经元的成熟，通过遗传易感性和环境暴露界面的神经发育过程导致疾病易感性增加。脑类器官是探索糖皮质激素对早期人类脑发育影响的宝贵转化资源。
