Hum Reprod. 2026 Jun 05. pii: deag078. [Epub ahead of print]
G Moser,
D Kummer,
M Gruber,
T Hartmann,
D Forstner,
J Guettler,
M Siwetz,
M Sundl,
C Daxboeck,
S Kienesberger,
J Kargl,
A Deutsch,
J Fessler,
B Huppertz,
J Feichtinger,
M Gauster.
STUDY QUESTION: Does the degree of extravillous trophoblast (EVT) invasion influence decidual tissue architecture and immune cell distribution in first-trimester decidua?
SUMMARY ANSWER: Areas of pronounced morphological changes have been identified at sites of strong EVT invasion in the decidua basalis-defined as 'remodeling lesions'-and are associated with a substantially reshaped immune cell landscape.
WHAT IS KNOWN ALREADY: During early human placental development, EVTs invade the decidua to facilitate placental attachment and nutrient supply to the fetus. EVT-driven decidual tissue restructuring and vascular adaptation are essential for establishing a functional fetal-maternal interface, to which the decidual microenvironment is thought to contribute substantially. However, the precise impact of the degree of EVT invasion on decidual architecture and immune cell distribution remains poorly understood, underscoring the need to elucidate how varying EVT abundances shape the morphological and cellular landscape of the decidual microenvironment.
STUDY DESIGN, SIZE, DURATION: First-trimester decidual tissue (n = 23, gestational age Weeks 7-9) was analyzed from women undergoing elective terminations of pregnancy between 2011 and 2023. Additionally, hematoxylin and eosin-stained sections from archival specimens (n = 11), obtained from three different sources, were included in the study.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Matched first-trimester decidua basalis and decidua parietalis samples from the same donors were analyzed through a comprehensive approach combining spatial transcriptomics, histomorphological characterization, and quantitative image analysis. Decidua sections were (i) categorized according to the degree of invasion, (ii) subjected to spatial transcriptomics, including integration with a previously published single-cell RNA-seq dataset, and (iii) quantitatively assessed on the protein level for selected immune cell populations with immunostaining and semi-automated image analysis. The study was complemented by (iv) an observer-based histological evaluation and (v) comprehensive staining series of consecutive decidua sections.
MAIN RESULTS AND THE ROLE OF CHANCE: Analyses revealed a characteristic tissue restructuring of the decidua and distinct spatial patterns of immune cell abundance in relation to the degree of EVT invasion. In strongly invaded decidual areas, we identified regions with pronounced morphological changes-defined as 'remodeling lesions'. These remodeling lesions typically displayed compromised tissue integrity, eroded blood vessels, extravasal erythrocytes, fibrin deposits, and a distinct gene expression profile, reflecting coagulation, fibrinolysis, and tissue restructuring. While we observed a decline in local immune cell populations-specifically T cells, macrophages, and decidual natural killer cells-with increasing EVT density, neutrophils were almost exclusively located within or in close proximity to remodeling lesions, indicating a substantially reshaped immune landscape.
LARGE SCALE DATA: Spatial transcriptomics data are available in the Gene Expression Omnibus repository under accession number GSE301306.
LIMITATIONS, REASONS FOR CAUTION: Studies using first-trimester placental tissues from elective terminations are inherently limited by surgical disruption of the intact (in toto) anatomical architecture of the tissue and the unknown pregnancy outcome. Spatial transcriptomics was performed on a limited number of tissue sections, and histological tissue sections represent just a snapshot, highlighting the limitations of such tissue-based analyses.
WIDER IMPLICATIONS OF THE FINDINGS: While blood leakage into the stromal tissue compartment has typically been documented for pathological conditions-such as large atherosclerotic plaques and tumors-we report such a scenario under physiological conditions for the early invaded decidua. We propose that strong EVT invasion induces remodeling lesions in the decidua basalis and also shapes the surrounding immune cell landscape. We further suggest that the occurrence of these remodeling lesions contributes to the establishment of a stable yet flexible basal plate and is thus necessary for a reliable connection between mother and placenta/fetus. It can be speculated that inadequate decidual tissue restructuring and vascular adaptation lead to pregnancy pathologies and complications such as placental abruption.
STUDY FUNDING/COMPETING INTEREST(S): G.M. was supported by the Austrian Science Fund (FWF): PAT9611123. M.G. was supported by the Austrian Science Fund (FWF): 10.55776/P35118 and 10.55776/I6907. This project has received funding from the European Union's Horizon Europe research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101169308 (funding supported M.G.). M.G., G.M., and J.F. were supported by the Medical University of Graz through the PhD program MolMed. J.F. and G.M. were supported by the COMET center acib: Next Generation Bioproduction (Project #98.311 and #95.802) is funded by BMIMI, BMWET, SFG, Standortagentur Tirol, Government of Lower Austria and Vienna Business Agency in the framework of COMET-Competence Centers for Excellent Technologies. The COMET-Funding Program is managed by the Austrian Research Promotion Agency FFG. The authors declare that they have no conflicts of interest related to this work.
Keywords: EVT invasion; EVTs; extravillous trophoblast; first-trimester decidua; immune microenvironment; placental anatomy; placental development; remodeling lesion; spatial transcriptomics; trophoblast invasion