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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.

Sec. Molecular and Cellular Reproduction

Volume 13 - 2025 | doi: 10.3389/fcell.2025.1636335

This article is part of the Research TopicExtracellular Vesicles Signaling in Embryogenesis and MorphogenesisView all 3 articles

Extracellular vesicles as prospective biological indicators for midgestational placental complications in the mouse

Provisionally accepted
  • 1McGill University, Montreal, Canada
  • 2Research Institute of the McGill University Health Centre, Montreal, Canada

The final, formatted version of the article will be published soon.

Placental dysfunction is associated with reproductive complications such as preeclampsia, intrauterine growth restriction, and preterm birth. Currently, the early diagnosis and intervention of these pathologies remain challenging due to the invasive nature of placental tissue sampling. Liquid biopsies of extracellular vesicles (EVs) released from the placenta have emerged as a prospective minimally invasive diagnostic strategy that could provide insight into the maternal-fetal interface because of the role EVs play in mediating placental development and function. However, the lack of information on EVs directly from placenta at disease onset has questioned the representativeness of placental EVs as pathological indicators. To address these concerns, this study assessed the accuracy with which tissue-derived D10.5 placental EVs could identify phenotypes exhibited by a reproductively challenged Nodal conditional knockout mouse model at mid-gestation. Implantation sites from mice with a uterine-specific knockdown of Nodal were examined from D8.5 to D14.5 utilizing histological analysis, western blotting, and RT-qPCR to characterize their mid-gestational phenotypes. Placental EVs were then isolated from D10.5 placenta using enzymatic digestion, differential centrifugation, filtration, and size exclusion chromatography. The final EV fractions were concentrated and validated with size analysis, canonical protein markers, and morphology assessment. Differential expression analysis across the EV samples was performed using proteomics and miRNA-Seq. Functional enrichment analysis of dysregulated EV factors was then completed using several gene ontology databases along with a literature review to determine whether placental EVs could indicate the reproductive abnormalities presented by the mutant mice.Uterine-specific deletion of Nodal resulted in IUGR and fetal loss in mutant dams. Decidualization and placentation defects were observed, including thinner decidual and placental tissues, impaired angiogenesis, and an altered junctional zone within the maternal-fetal interface. Bioinformatics analysis of EV cargo identified 31 differentially expressed proteins and 10 miRNAs specifically linked to placental development, oxidative stress, angiogenesis, and immunomodulation. Notably, 15 of these proteins and 6 of these miRNAs have been previously associated with pregnancy complications, further supporting the prospects of placental EVs as biomarkers for various placental diseases.These findings suggest that placental EVs can reflect compromised placental function and could serve as pathological indicators for the early detection of pregnancy complications.

Keywords: Pregnancy, Placenta, Proteomics, miRNAs, Nodal, Exosomes, EVs Original Research Article

Received: 27 May 2025; Accepted: 07 Jul 2025.

Copyright: © 2025 Dufort, Lee, Kazemi, Shafiei, Yull, Rana, Tawil, Montermini and Rak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Daniel Dufort, McGill University, Montreal, Canada

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