Human brain organoid model of maternal immune activation identifies radial glia cells as selectively vulnerable

Abstract

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.

Transcriptional and Cellular Response of hiPSC-derived Microglia-Neural Progenitor Co-Cultures Exposed to IL-6

“…Moreover, concerning the enduring effects of short-term IL-6 exposure during the NPC stage, our findings revealed no marked changes in the differentiation paths of forebrain NPCs into diverse cell types. This contrasts with earlier findings in hiPSC-derived neuronal cultures that cell-fate acquisition is affected by IL-6 (Sarieva, Kagermeier, et al ., 2023), but noting that Sarieva at colleagues (2023) stimulated their cultures with hyper-IL-6 for five days. Furthermore, IL-6 exposure did not significantly affect synaptic densities or intensities in post-mitotic neurons, which was also unexpected given previous research suggesting that early IL-6 exposure has the potential to alter synaptogenesis in the hippocampus of a rodent model, perhaps highlighting potential regional or species differences in the effects of IL-6 on synaptogenesis (Samuelsson et al ., 2006; Mirabella et al ., 2021).…”

“…Our study suggests that a more prolonged cytokine exposure remains important to test in order to induce substantial changes in NPCs, such as the 5-day exposure to brain organoids by Sarieva and colleagues (2023), given none were seen in response to the post IL-6 MGL-secreted microenvironment. Such extended exposure could more closely mimic the physiological conditions of a long-term prenatal infection, potentially offering a more realistic model for studying the effects of maternal immune activation on foetal brain development (Sarieva, Kagermeier, et al ., 2023).…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted December 22, 2023. ; https://doi.org/10.1101/2023.12.21.572748 doi: bioRxiv preprint substantial changes in NPCs, such as the 5-day exposure to brain organoids by Sarieva and colleagues (2023), given none were seen in response to the post IL-6 MGL-secreted microenvironment. Such extended exposure could more closely mimic the physiological conditions of a long-term prenatal infection, potentially offering a more realistic model for studying the effects of maternal immune activation on foetal brain development (Sarieva, Kagermeier, et al, 2023).…”

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

“…Genetic ablation of the IL-6 receptor on placental trophoblasts in poly I:C-challenged dams prevented offspring behavioral abnormalities and neuropathologies [85]. Recent studies further bolster the idea that IL-6 is capable of directly mediating brain development via prenatal programming of synaptogenesis (as seen in mice) and via dysregulation of radial glia (as seen in human brain organoids) [86,87]. There is also strong evidence documenting the negative effects of anti-viral interferon signaling on placental and fetal development during maternal infection [88].…”

Neuroimmune mechanisms in autism etiology - untangling a complex problem using human cellular models

“…The human fetal brain expresses the canonical IL-6 receptors in microglia. However, GP130, which is a non-canonical receptor for IL-6, is highly expressed in radial glial cells, a major NPC subtype [ 184 ]. This suggests a cell-type specific function for IL-6 downstream signaling in radial glia.…”