母体免疫激活 (MIA) 通过炎症细胞因子（包括白细胞介素 6 (IL-6)）增加后代神经发育障碍的风险。因此，我们的目标是建立人类二维（2D）体外神经模型，以研究 IL-6 暴露对神经发育的影响。 IL-6信号转导需要两种受体：白细胞介素6信号转导器(IL6ST)和白细胞介素6受体(IL6R)。产前，神经细胞缺乏 IL6R，因此不能引发顺式 IL-6 信号传导，但小胶质细胞可以反式提供 IL6R。我们在此证明永生化人类神经祖细胞 (NPC) 系 ReNCell CX 表达 IL6ST 并引发顺式和反式 IL-6 信号传导，限制了其作为 MIA 模型的使用。相比之下，诱导多能干细胞 (iPSC) 衍生的 NPC 仅激活反式 IL-6 级联。正如动物模型中所证明的那样，反式 IL-6 级联的激活不会导致 iPSC 衍生的 NPC 或 ReNCell CX 的增殖增加。 iPSC 衍生的 NPC 响应 IL-6 信号传导上调 NR2F1 表达，与类器官中的类似实验一致。因此，iPSC 衍生的 NPC 可用于模拟 2D 培养物中响应 MIA 的基因表达变化。© 2023。由 The Company of Biologies Ltd 出版。

Maternal immune activation (MIA) increases the risks for neurodevelopmental disorders in offspring through inflammatory cytokines, including interleukin-6 (IL-6). We therefore aimed to establish a human two-dimensional (2D) in vitro neural model to investigate the effects of IL-6 exposure on neurodevelopment. IL-6 signal transduction requires two receptors: interleukin-6 signal transducer (IL6ST) and interleukin-6 receptor (IL6R). Prenatally, neural cells lack IL6R, and hence cannot elicit cis IL-6 signaling, but IL6R can be provided by microglia in trans. We demonstrate here that an immortalized human neural progenitor cell (NPC) line, ReNCell CX, expresses IL6ST and elicits both cis and trans IL-6 signaling, limiting its use as a model of MIA. In contrast, induced pluripotent stem cell (iPSC)-derived NPCs only activate the IL-6 cascade in trans. Activation of the trans IL-6 cascade did not result in increased proliferation of iPSC-derived NPCs or ReNCell CX, as has been demonstrated in animal models. iPSC-derived NPCs upregulated NR2F1 expression in response to IL-6 signaling in line with analogous experiments in organoids. Thus, iPSC-derived NPCs can be used to model gene expression changes in response to MIA in 2D cultures.© 2023. Published by The Company of Biologists Ltd.