Circulating extracellular vesicles in healthy and pathological pregnancies: A scoping review of methodology, rigour and results

Abstract

Extracellular vesicles (EVs) play a crucial role in pregnancy, revealed by the presence of placental‐derived EVs in maternal blood, their in vitro functionality, and their altered cargo in pregnancy pathologies. These EVs are thought to be involved in the development of pregnancy pathologies, such as pre‐eclampsia, pre‐term birth, and fetal growth restriction, and have been suggested as a source of biomarkers for gestational diseases. However, to accurately interpret their function and biomarker potential, it is necessary to critically evaluate the EV isolation and characterization methodologies used in pregnant cohorts. In this systematic scoping review, we collated the results from 152 studies that have investigated EVs in the blood of pregnant women, and provide a detailed analysis of the EV isolation and characterization methodologies used. Our findings indicate an overall increase in EV concentrations in pregnant compared to non‐pregnant individuals, an increased EV count as gestation progresses, and an increased EV count in some pregnancy pathologies. We highlight the need for improved standardization of methodology, greater focus on gestational changes in EV concentrations, and further investigations into the functionality of EVs. Our review suggests that EVs hold great promise as diagnostic and translational tools for gestational diseases. However, to fully realize their potential, it is crucial to improve the standardization and reliability of EV isolation and characterization methodologies, and to gain a better understanding of their functional roles in pregnancy pathologies.

Extracellular vesicles alter trophoblast function in pregnancies complicated by COVID-19

“…Perturbation of normal trophoblast function, as caused by altered EV signaling, underlies the placental dysfunction that contributes to many pregnancy complications (34)(35)(36)(37)(38)(39)(40)(41). Importantly, EV characteristics such as number and cargo are altered in multiple pregnancy complications (42).…”

The ‘communicatome’ of pregnancy: spotlight on cellular and extravesicular chimerism

“…These include the regulation of maternal homeostasis during implantation (Godakumara et al, 2021 ), the maintenance of pregnancy (Pap et al, 2008 ) and the onset of parturition (Menon et al, 2020 ). Noteworthy, limitations resulting from the different isolation methods and terminology of EVs during pregnancy have recently been unearthed (Barnes et al, 2023 ). These impair direct comparison and interpretation of insights on EVs during pregnancy between studies.…”

Differential proteomics of circulating extracellular vesicles of placental origin isolated from women with early‐onset preeclampsia reveal aberrant innate immune and hemostasis processes

“…However, understanding their functional roles along with standardizing and verifying EV isolation and characterization techniques is crucial. 27 In the current study, we used quantitative tandem mass spectrometry to investigate the distinct protein profiles of PLAP + and HLA-G + circulating placental EVs obtained from normotensive pregnant and EOPE women for disease-related biomarker identification. To obtain an enriched population of circulating placental EVs, a population consisting of EVs from both placental cell types was extracted using a combination of human leukocyte antigen G (HLA-G), an extravillous trophoblast (EVT) enriched marker, and placental alkaline phosphatase (PLAP), syncytiotrophoblast enriched marker.…”

“…These vesicles are therefore potential diagnostic tools for various gestational diseases. However, understanding their functional roles along with standardizing and verifying EV isolation and characterization techniques is crucial 27 …”