Objective:

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.

Methods:

The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development.

Results:

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.

Conclusions:

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.

中文翻译：

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糖皮质激素受体激活对发育中大脑的细胞类型特异性影响：脑类器官研究

客观的：

糖皮质激素受体 (GR) 激活的微调平衡对于器官形成至关重要，干扰会影响许多健康结果。在子宫内，糖皮质激素与大脑相关的负面结果有关，但潜在机制尚不清楚，尤其是在细胞类型特异性影响方面。一种胎儿人脑发育的体外模型，即诱导人多能干细胞 (hiPSC) 衍生的大脑类器官，用于测试大脑类器官是否适合研究产前糖皮质激素暴露对大脑发育的影响。

方法：

GR 被合成的糖皮质激素地塞米松激活，并且在整个开发过程中使用单细胞转录组学绘制了效果图。

结果：

GR 在所有细胞类型中均有表达，随着发育过程的表达水平不断提高。它的激活不仅引起细胞核易位和对已知 GR 调节通路的预期影响，而且神经元和祖细胞显示出对分化和成熟相关转录物的靶向调节。在神经元中独特的是，差异表达的转录本显着丰富了与行为相关表型和疾病相关的基因。这种人类神经元糖皮质激素反应谱在三个独立的 hiPSC 系的类器官中得到验证，这些 hiPSC 系从男性和女性供体的不同来源组织重新编程。

结论：

这些发现表明，过多的糖皮质激素暴露可能会干扰子宫内的神经元成熟，从而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大脑发育影响的宝贵转化资源。