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Maternal immune activation (MIA) during critical windows of gestation is correlated with long-term neurodevelopmental deficits in the offspring, including increased risk for autism spectrum disorder (ASD) in humans. Interleukin 6 (IL-6) derived from the gestational parent is one of the major molecular mediators by which MIA alters the developing brain. In this study, we establish a human three-dimensional (3D) in vitro model of MIA by treating induced pluripotent stem cell-derived dorsal forebrain organoids with a constitutively active form of IL-6, Hyper-IL-6. We validate our model by showing that dorsal forebrain organoids express the molecular machinery necessary for responding to Hyper-IL-6 and activate STAT signaling upon Hyper-IL-6 treatment. RNA sequencing analysis reveals the upregulation of major histocompatibility complex class I (MHCI) genes in response to Hyper-IL-6 exposure, which have been implicated with ASD. We find a small increase in the proportion of radial glia cells after Hyper-IL-6 treatment through immunohistochemistry and single-cell RNA-sequencing. We further show that radial glia cells are the cell type with the highest number of differentially expressed genes, and Hyper-IL-6 treatment leads to the downregulation of genes related to protein translation in line with a mouse model of MIA. Additionally, we identify differentially expressed genes not found in mouse models of MIA, which might drive species-specific responses to MIA. Finally, we show abnormal cortical layering as a long-term consequence of Hyper-IL-6 treatment. In summary, we establish a human 3D model of MIA, which can be used to study the cellular and molecular mechanisms underlying the increased risk for developing disorders such as ASD.
Sarieva et al. (Mon,) studied this question.