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Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells

ABSTRACT: Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells

PROVIDER: PRJNA1166124 | ENA |

REPOSITORIES: ENA

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Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells

Project description:Background: Prenatal exposure to elevated interleukin (IL)-6 levels is associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ), autism spectrum condition (ASC) and bipolar disorder (BD). Although rodent models provide causal evidence for this association, we lack a detailed understanding of the cellular and molecular mechanisms in human model systems. To close this gap, we characterized the response of human induced pluripotent stem cell (hiPSC-)derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture. Results: We observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both protein and transcript levels due to the absence of IL6R expression and soluble (s)IL6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL6, JMJD3 and IL10 expression in MGL, confirming activation of canonical IL6Ra signaling. Bulk RNAseq identified 156 up-regulated genes (FDR < 0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an up-regulated gene set from human post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility, consistent with gene ontology pathways highlighted from the RNAseq data and replicating rodent model indications that IRF8 regulates microglial motility. Finally, IL-6 induces MGLs to secrete CCL1, CXCL1, MIP-1α/β, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 after 3h and 24h. Conclusion: Our data provide evidence for cell specific effects of acute IL-6 exposure in a human model system, ultimately suggesting that microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.

2024-09-30 | GSE278224 | GEO

Analysis of hiPSC-derived microglia compared to other cell types

Project description:We performed RNA-seq analysis to compare hiPSC-derived microglia with hiPSCs, NPCs and human fetal microglia. We analyzed additional RNA-seq data from published human brain microglial cells and other monocytic cells to offer further support for the identity of our hiMG.

2021-03-18 | GSE169065 | GEO

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

Project description:Elevated interleukin (IL-)6 levels during prenatal development have been linked to increased risk for neurodevelopmental disorders (NDD) in the offspring, but the mechanism remains unclear. Human-induced pluripotent stem cell (hiPSC) models offer a valuable tool to study the effects of IL-6 on features relevant for human neurodevelopment in vitro. We previously reported that hiPSC-derived microglia-like cells (MGLs) respond to IL-6, but neural progenitor cells (NPCs) in monoculture do not. Therefore, we investigated whether co-culturing hiPSC-derived MGLs with NPCs would trigger a cellular response to IL-6 stimulation via secreted factors from the MGLs. Using N=4 donor lines without psychiatric diagnosis, we first confirmed that NPCs can respond to IL-6 through trans-signalling when recombinant IL-6Ra is present, and that this response is dose-dependent. MGLs secreted soluble IL-6R, but at lower levels than found in vivo and below that needed to activate trans-signalling in NPCs. Whilst transcriptomic and secretome analysis confirmed that MGLs undergo substantial transcriptomic changes after IL-6 exposure and subsequently secrete a cytokine milieu, NPCs in co-culture with MGLs exhibited a minimal transcriptional response. Furthermore, there were no significant cell fate-acquisition changes when differentiated into post-mitotic cultures, nor alterations in synaptic densities in mature neurons. These findings highlight the need to investigate if trans-IL-6 signalling to NPCs is a relevant disease mechanism linking prenatal IL-6 exposure to increased risk for psychiatric disorders. Moreover, our findings underscore the importance of establishing more complex in vitro human models with diverse cell types, which may show cell-specific responses to microglia-released cytokines to fully understand how IL-6 exposure may influence human neurodevelopment.

2024-10-14 | GSE279125 | GEO

Analysis of hiPSC-derived microglia compared to other cell types

Project description:Analysis of hiPSC-derived microglia compared to other cell types

| PRJNA715096 | ENA

PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids

Project description:PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids

| PRJNA787104 | ENA

Porphyromonas gingivalis triggers microglia activation and neurodegenerative processes through NOX4

Project description:Porphyromonas gingivalis triggers microglia activation and neurodegenerative processes through NOX4

| PRJNA1147160 | ENA

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

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

| PRJNA1170926 | ENA

PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids [scRNA-Seq]

Project description:PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids [scRNA-Seq]

| PRJNA787111 | ENA

PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids [RNA-Seq]

Project description:PAX6-positive microglia evolve locally in hiPSC-derived ocular organoids [RNA-Seq]

| PRJNA787110 | ENA

T cell mediated microglia activation triggers myelin pathology in a model of amyloidosis

Project description:Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer’s disease (AD) remains uncertain, despite age being a major risk factor. Using a mouse model of AD, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8+ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis.

2024-05-10 | GSE243018 | GEO

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