Maternal immune activation (MIA) reshapes placental development

The placenta coordinates maternal–fetal exchange, immune regulation, and fetal development, making it vulnerable to inflammation during pregnancy. Maternal immune activation (MIA) is a widely recognized risk factor for adverse fetal development, yet how early-gestational MIA affects placental development has remained unclear.

In this study published in Genes & Diseases, researchers from Chongqing Medical University investigated the spatiotemporal transcriptomic dynamics and phenotypic responses of the murine placenta to MIA.

Using an early MIA model established by administering lipopolysaccharide (LPS) at embryonic day 7.5 (E7.5), the researchers generated a high-resolution spatiotemporal transcriptomic atlas comprising 16 placental samples across four developmental stages from E10.5 to E16.5. Their custom spatial transcriptomics platform, developed using DBiT-seq and MISAR-seq principles, integrated microfluidic spatial barcoding with unsupervised clustering at a 30-µm resolution, successfully delineating five spatial domains: the myometrium, decidua, junctional zone, labyrinth, and yolk sac.

Combined histological, immunofluorescence, and ELISA assessments showed that acute MIA induced a transient maternal pro-inflammatory state, with elevated TNF-α and IL-10, followed by a transition to a conditioned tolerogenic profile by E10.5. Despite this immunological rebalancing, MIA resulted in late-gestational fetal growth restriction, fetal loss, and pronounced placental structural remodeling, characterized by reductions in the decidua and junctional zone alongside expansion of the labyrinth at E18.5. These deficits were more pronounced in males.
Stratified spatial and non-negative matrix factorization analyses demonstrated that early-gestational MIA persistently perturbed transcriptional programs in the junctional zone and labyrinth.
MIA increased programs related to inflammation, hypoxia, apoptosis, and leukocyte migration while suppressing DNA repair and cell-cycle regulation. Proliferative labyrinthine programs may represent a compensatory response to earlier injury.

Furthermore, sex-stratified profiling uncovered marked sexual dimorphism, with male placentas exhibiting heightened transcriptomic and phenotypic inflammatory responses accompanied by stronger HMGB1 immunoreactivity and elevated lipid storage signatures, whereas female placentas displayed enhanced labyrinthine angiogenesis with higher CD31-positive endothelial abundance, increased glycogen retention within the junctional zone, and distinct transcriptomic signatures of nutrient transport. These differences may contribute to greater growth impairment in males.

Pseudotime trajectory and ligand–receptor interaction analyses within the junctional zone suggested that MIA induced premature differentiation and stress-associated microenvironmental remodeling, marked by upregulation of extracellular matrix and integrin-family genes. The authors identified ITGB1 as a central adhesion-related gene, demonstrating that LPS increased ITGB1 expression in human trophoblasts, while its knockdown aggravated LPS-induced reductions in viability and migration. These findings support its proposed role as a candidate mediator of a putative adaptive response that may help maintain trophoblast survival and motility.

This study provides a comprehensive spatiotemporal transcriptomic atlas showing that early-gestational MIA drives persistent structural remodeling, sexually dimorphic metabolic adaptations, and compensatory extracellular matrix responses in the placenta. It further identifies ITGB1 as a candidate mediator of placental adaptation to inflammatory stress and provides cross-species insights into inflammation-associated placental dysfunction.

Reference

Title of the original paper: Spatiotemporal transcriptomics reveals placental development responses under maternal immune activation
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102246

Funding Information:
National Natural Science Foundation of China (No. 82341112, 82372356)
Postdoctoral Fellowship Program of CPSF (China) (No. GZC20233352)
China Postdoctoral Science Foundation (No. 2024T171105)
CQMU Program for Youth Innovation in Future Medicine (China) (No. W0161)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 10.4 | Impact Factor: 14.6

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(A) Schematic illustration of the experimental design for maternal immune activation (MIA) mouse model construction and sample collection. (B) Maternal weight throughout gestation in saline- and LPS-treated groups (n = 5 dams/group). (C) Maternal serum concentrations of TNF-α and IL-10 cytokines (n = 4 dams/embryo day/group) measured by ELISA assay. (D) The IL-10/TNF-α ratio in maternal serum of the saline (top) and LPS (bottom) groups. (E) Representative images of embryos in the uterus from saline- and LPS-treated mice at different development stages. (F) The miscarriage rate of pregnant mice in the indicated groups. (G–J) Comparison of fetal weight (G), crown-rump length (H), placental weight (I), and placental efficiency (J) at E18.5 between the saline- and LPS-treated groups (n = 23 offspring/matched placenta from 3 saline litters, and n = 14 offspring/matched placentas from 3 LPS litters). (K) Average proportions of the decidua (De), junctional zone (JZ), and labyrinth (Lab) areas relative to the total placental area at E18.5 (n = 16 placentas from 3 saline litters, and n = 14 placentas from 3 LPS litters). All data are represented as the mean ± standard deviation. Statistical significance was calculated by Student's t-test (G–J), one-way repeated-measures ANOVA followed by Sidak's multiple comparisons test (B), or one-way ANOVA followed by Sidak's multiple comparisons test (C, K).
(A) Gene set scores of the inflammatory response pathway from E10.5 to E16.5 in the saline and LPS groups. (B) Bar chart displaying the number of differentially expressed genes (DEGs) (saline vs. LPS) across spatial domains. (C) Correlation analysis of gene set scores between the inflammatory response and seven DEG-related signaling pathways across spatial domains. (D) UMAP representation of 20 factors in the saline and LPS groups. (E) Comparison of NMF weights for factors 2, 4, and 13 in the indicated spatial domains between the saline and LPS groups. (F) Spatial expression patterns of factors 2, 4, and 13 from E10.5 to E16.5 in the saline and LPS groups. (G) Functional enrichment using the top 50 weighted genes associated with factors 2, 4, and 13.
(A) Network visualization of 10 hub genes associated with six placenta-associated pregnancy disorders. The octagonal nodes represent diseases, and the oval nodes represent genes. An edge indicates that the corresponding hub gene is present in the curated gene list associated with a specific disorder. (B) Gene expression of 10 hub genes in the human placental cell line BeWo. (C, D) Gene expression of ITGB1 in BeWo and HTR-8/SVneo cell lines after siRNA transfection. (E, F) Cell viability assay after 24 h treatment with LPS or saline with BeWo and HTR-8/SVneo cell lines. (G–J) Representative images (0 h and 24 h) and wound healing rates are shown for BeWo (G, H) and HTR-8/SVneo (I, J) cell lines under different treatments. All experiments were conducted independently three times. Statistical significance calculated by Student's t-test (B–D) with Benjamini–Hochberg FDR correction for multiple testing (B), or two-way ANOVA followed by Tukey's multiple comparisons test (E, F, H, J)

30/10/2026 Compuscript Ltd

Regions: Europe, Ireland, United Kingdom, Asia, China

Keywords: Science, Life Sciences

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