Kirkpatrick Madeline, Mandal Gargi, Elhadidy Ismail, Mariani Nicole, Priestley Kristi, Pariante Carmine M, Borsini Alessandra
Department of Psychological Medicine, Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
Mol Psychiatry. 2025 Apr;30(4):1689-1707. doi: 10.1038/s41380-024-02866-1. Epub 2024 Dec 5.
Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the in-utero environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.
The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.
Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.
Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.
孕期抑郁症可能会增加后代患精神疾病的易感性，这可能是通过将母体升高的皮质醇和细胞因子传递到子宫内环境实现的。然而，确切的细胞和分子机制在很大程度上尚不清楚。动物研究可以在系统水平上呈现这种复杂的病理生理学，但成本高昂且在伦理上具有挑战性。虽然体外模型更简单，但提供了高通量的机会。因此，本系统综述整合了与孕期抑郁症相关的体外模型的研究结果，以生成新的假设和干预靶点。
系统分析涵盖了研究糖皮质激素或细胞因子对胎盘或胎儿神经祖细胞（NPC）的挑战的研究，无论是否同时使用性激素进行联合治疗。
在纳入的50项研究中，11项使用了胎盘细胞，39项使用了NPC；令人惊讶的是，只有一项使用了雌激素和皮质醇的组合，没有研究将胎盘细胞和NPC结合使用。在胎盘细胞中，皮质醇或细胞因子降低了营养转运蛋白的表达和类固醇生成酶的活性，并增加了细胞因子的产生。NPC通过特定的分子途径，即抑制刺猬信号通路和激活犬尿氨酸途径，表现出增殖和分化的减少。在这些细胞中，研究还强调了应激和炎症途径的表观遗传启动。
总体而言，结果表明应激和炎症不仅对胎盘向胎儿的营养物质和激素调节产生不利影响，还通过胎盘炎症增加激活下游途径，最终对胎儿神经发生产生不利影响。未来的研究应调查性激素如何调节这些机制，以期开发针对孕期抑郁症的靶向治疗方法。
