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Heterogeneity in Inflammatory Responses to Endotoxin at the Feto-Maternal Interface

ABSTRACT: The feto-maternal interface (FMi), comprising fetal chorionic trophoblast cells (CTCs) and maternal decidual stromal cells (DECs), plays a critical role in providing immune tolerance during pregnancy. Intrauterine inflammation is a major trigger of adverse outcomes such as preterm birth, yet the cell-specific inflammatory responses at the FMi leading to immune intolerance show heterogeneity; however, the inflammatory characteristics remain poorly defined. To investigate the differential inflammatory responses of fetal and maternal cell populations at the FMi upon exposure to endotoxin (lipopolysaccharide, LPS), and to delineate molecular pathways underlying the heterogeneity in the inflammatory signature. Primary CTCs and DECs were isolated from human term fetal membrane tissues. Cells were treated with LPS (100 ng/mL) for 48 hours. Transcriptomic profiling was performed to assess differentially expressed genes and pathway enrichment. Inflammatory cytokines were quantified using multiplex immunoassays. Protein-level responses were validated using western blotting. Regulatory network analysis identified upstream drivers of cell-specific responses. LPS induced a robust and uniform inflammatory response in DECs, marked by high expression of pro-inflammatory chemokines, and prostaglandin biosynthesis enzymes associated with adverse pregnancy outcomes. In contrast, CTCs showed an attenuated response, characterized by selective induction of stress-associated genes with minimal activation of classical inflammatory pathways. Transcriptomic network analysis revealed distinct cell-type-specific regulatory hubs, including STAT1 and IRF7 in DECs and RELA and MYD88 in CTCs. Notably, DECs also activated anti-inflammatory signaling and pyroptosis-related pathways, which were largely absent in CTCs, indicating compartmentalized immune regulation at the feto-maternal interface. Our findings reveal a fundamental heterogeneity in inflammatory responses at the FMi, with maternal cells exhibiting greater sensitivity to endotoxin-induced activation compared to fetal chorion trophoblast cells. These differential reactivity responses may be an evolved mechanism to shield the fetus from excessive inflammation or to impede the inflammatory onslaught from reaching the fetus. Understanding cell-specific responses provides a foundation for understanding tolerance and mediators of intolerance at the FMi and identifying potential targets for therapeutic strategies in inflammation-associated pregnancy complications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316086 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:Epidemiological studies suggest that maternal exposures to environmental chemicals may be linked to spontaneous preterm birth. Mechanistic studies are needed to provide support to these hypotheses; however, existing in vitro models do not replicate the human feto-maternal barriers beyond placenta. The recently developed four-cell (human immortalized maternal decidua, chorion trophoblast, amnion mesenchymal, and amnion epithelial cells) Feto-Maternal interface Organ-On-Chip (FMi-OOC) enables studies of chemical effects on the decidua, chorion and amnion, maternal and fetal tissues that are critically important for maintaining full-term pregnancy. We tested four environmental compounds that have been associated with preterm birth – dichlorodiphenyltrichloroethane (DDT-o,p’), bisphenol A (BPA), 2,2'4,4'-tetrabromodiphenyl ether (PBDE-47), and perfluorooctanoic acid (PFOA). First, concentration-response effects of these chemicals were tested on maternal decidua cells in 96-well plates. Then, experiments were performed in FMi-OOC containing four fetal-maternal cell types arranged into four concentric chambers, mimicking the in utero cell topology. Compounds were added to the maternal (i.e., decidua) chambers, and chemical propagation, cell viability and proinflammatory cytokines (IL-6, IL-8, GM-CSF, TNF-α) were measured in decidua, chorion trophoblast, amnion mesenchymal, and amnion epithelial cells for up to 72 hrs. Minimal propagation of test compounds to fetal chambers was observed and tested concentrations were non-cytotoxic. Treatment-associated increase in cytokine production was observed for all compounds, with PFOA and BPA showing the strongest effects and amnion epithelial cells being the most responsive. We demonstrate how the multi-cellular FMi-OOC model can be used to study paracrine signaling in complex human tissues such as fetal-maternal interface. In addition, these studies provide mechanistic support for the plausibility of the epidemiological associations between maternal exposures to tested compounds and preterm birth. We show that upon maternal exposure, albeit at concentrations exceeding reported human blood levels by 1 to 2 orders of magnitude, fetal membranes attain a pro-inflammatory state, a potential trigger for preterm birth.

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Heterogeneity in Inflammatory Responses to Endotoxin at the Feto-Maternal Interface

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