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
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