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Antoniadis, P.; Duica, F. Extracellular Vesicles in Normal Pregnancy. Encyclopedia. Available online: https://encyclopedia.pub/entry/8928 (accessed on 07 July 2024).
Antoniadis P, Duica F. Extracellular Vesicles in Normal Pregnancy. Encyclopedia. Available at: https://encyclopedia.pub/entry/8928. Accessed July 07, 2024.
Antoniadis, Panagiotis, Florentina Duica. "Extracellular Vesicles in Normal Pregnancy" Encyclopedia, https://encyclopedia.pub/entry/8928 (accessed July 07, 2024).
Antoniadis, P., & Duica, F. (2021, April 22). Extracellular Vesicles in Normal Pregnancy. In Encyclopedia. https://encyclopedia.pub/entry/8928
Antoniadis, Panagiotis and Florentina Duica. "Extracellular Vesicles in Normal Pregnancy." Encyclopedia. Web. 22 April, 2021.
Extracellular Vesicles in Normal Pregnancy
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22083904

Extracellular vesicles (EVs) are small vesicles ranging from 20–200 nm to 10 μm in diameter that are discharged and taken in by many different types of cells. Depending on the nature and quantity of their content—which generally includes proteins, lipids as well as microRNAs (miRNAs), messenger-RNA (mRNA), and DNA—these particles can bring about functional modifications in the receiving cells. During pregnancy, placenta and/or fetal-derived EVs have recently been isolated, eliciting interest in discovering their clinical significance. 

extracellular vesicles placenta Nanovesicles

1. Introduction

Pregnancy, an efficiently regulated physiological process by which women give birth to offspring, is characterized by numerous adaptive changes—including, among others, anatomical, hormonal, metabolic, immunological and cardiovascular adjustments. Perhaps the most substantial, changes in the endocrine system help ensure the proper development of the growing fetus, particularly with the aid of the fetoplacental unit, which acts both as a meaningful hormone source and an efficient tissue barrier [1].While most pregnancies progress smoothly, culminating in successful delivery, the wellbeing of the mother and/or the fetus can be affected by various abnormalities occurring during gestation. The most common pregnancy complications refer to gestational hypertension, gestational diabetes mellitus, maternal systemic inflammation, infections, premature delivery, and fetal growth restriction [2][3][4]. Additionally, the physiological evolution of pregnancy can also be adversely influenced by congenital anomalies occurring during intrauterine life, such as structural chromosomal abnormalities, heart defects, and neural tube defects [5][6][7]. Furthermore, these complications not only increase the odds of adverse pregnancy outcomes, but also impact the later development of the newborn, and may result in various maternal afflictions following parturition, such as hypertension or diabetes [8][9][10]. At present, the diagnosis of these conditions mainly relies on hematological tests and ultrasound screening, routine blood pressure monitoring and proteinuria tests for hypertension and pre-eclampsia, along with blood glucose and fasting blood glucose levels measuring for gestational diabetes [11]. While repeatedly proven reliable, it is not rare that, by these means, anomalies are not detected in the optimal timeframe for ensuring favorable outcome following clinical intervention. Therefore, the development and use of novel non-invasive biomarkers for timely diagnosis of pregnancy-related complications and/or fetal anomalies is critical in the current setting of increased perinatal morbidity and mortality associated with pregnancy complications. To this extent, the quickly emerging field of extracellular vesicle (EV) research holds strong evidence for the use of its components as non-invasive, accurate biological signatures.Extracellular vesicles are cell-derived particles sheathed in a lipid bilayer that are naturally secreted into the extracellular space [12]. Though their functions often overlap, various subtypes have been suggested, with the three main established categories consisting of exosomes, ectosomes or microvesicles, and apoptotic bodies [13]. Exosomes vary in size, typically ranging from 30 to 150 nm in diameter [14][15], and are generated by the inward expansion of the endosome membrane, leading to the formation of multivesicular bodies (MVBs) rich in intraluminal vesicles (ILVs). When the MVB binds to the plasma membrane, ILVs are discharged in the form of exosomes [16][17]. Ectosomes, on the other hand, are commonly larger in size, reaching up to 1 μm in diameter [14][18][19], and are formed by the outward bulging of the plasma membrane, with the aid of cytoskeletal filaments [20][21]. Apoptotic bodies have been reported to reach up to 5000 nm in size [22], occurring as a result of cellular death accompanied by structural changes such as contraction and apoptotic blebbing [23]. The formation and discharge of MVBs and exosomes take place under the strict control of the endosomal sorting complexes required for transport (ESCRT) proteins [24][25][26], and are thought to be facilitated by certain growth factors [27]. Apart from ESCRT proteins, EVs also contain a group of marker proteins with no relation to the origin cell, including programmed cell death 6-interacting protein (PDCD6IP/Alix), tumor susceptibility gene 101 (TSG101), heat shock cognate protein 70 (HSC70), heat shock protein 90β (HSP90β), tetraspanin 28 (TSPAN28/CD81), tetraspanin 29 (TSPAN29/CD9), and tetraspanin 30 (TSPAN30/CD63) [28][29]. Tetraspanins are membrane proteins containing four transmembrane domains that play important roles in the fabrication and biosynthesis of EVs [30][31]. Further on, within their cargo, they also carry certain bioactive lipids and prostaglandins [32], along with RNA in the form of messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA) [33], and interestingly, little or no DNA. Ectosomes, on the other hand, differentiate themselves by markers such as annexin V, selectin, membrane type 1-matrix metalloproteinase (MT1-MMP), CD40, and flotillin-2 [19][34], while apoptotic bodies are rich in DNA fragments, intact organelles, histones, and annexin V [21][35].The International Society for Extracellular Vesicles (ISEV) currently recommends the use of the generic term ‘extracellular vesicle’, since establishing the exact biogenesis of the discussed particle is a difficult task. Furthermore, it is also suggested that authors rather describe the size, biochemical composition and origin of the EV, rather than erroneously attributing it a subtype [17]. Additionally, in order to confirm the presence of EVs, ISEV recommends identifying the presence of three categories of markers common to all EVs, as highlighted in Table 1.

Table 1. Markers that confirm the presence of EVs.

Category I Category II Category III
GPI-anchored or transmembrane proteins, demonstrating the lipid bilayer of the EV Cytosolic proteins in eukaryotic cells and Gram-positive bacteria
Periplasmic proteins in Gram-negative bacteria		 Constituents of non-EV factors that help evaluate the degree of contamination of the sample (e.g., APOA1/2, APOB, albumin, UMOD)

Due to high degree of heterogeny of these molecules, numerous isolation and identification methods have been developed, including labeling technologies such as flow cytometry, immunoelectron microscopy, or western blot for specific markers [36][37]. Some of the most common isolation and detection approaches used to evaluate the pregnancy-related nanovesicles have been summarized in Table 2 and Table 3, along with some of their advantages and disadvantages.Due to high degree of heterogeny of these molecules, numerous isolation and identification methods have been developed, including labeling technologies such as flow cytometry, immunoelectron microscopy, or western blot for specific markers [36][37]. Some of the most common isolation and detection approaches used to evaluate the pregnancy-related nanovesicles have been summarized in Table 2 and Table 3, along with some of their advantages and disadvantages.

Table 2. Isolation methods used in the detection of pregnancy-related EVs.

Biological Sample Potential Interfering Factors Isolation, Separation and Concentration Techniques Characteristics References
Plasma/serum of pregnant women Pre-/postprandial status
Medication
Sample volume
Container type
Processing time Choice of anticoagulant		 Differential centrifugation
Sequential centrifugation
Ultracentrifugation
Ultrafiltration		 Standard protocol for EVs isolation from biological fluids.
Requires additional steps for purification of pregnancy-associated EVs from other vesicles and co-isolated proteins		 [38][39][40]
Fluid from cultured placental tissue explants
Syncytiotrophoblast		 Specific infectious and noninfectious diseases
Technical factors
Storage and processing		 Differential centrifugations
Ultracentrifugation
Ultrafiltration
Chromatographic/immunosorbent procedure
Size exclusion chromatography
Precipitation
Immunoaffinity-based capture		 Used to study the composition and biological roles of placental EVs in normal and pathological pregnancies.
Requires ex vivo cultures of placental explants at different
gestational ages.
Techniques for biological samples collection may damage the products of conception		 [38][41][42]
Placental perfusate
Placental homogenate		 Specific infectious and noninfectious diseases
Technical factors
Storage and processing		 Differential centrifugation
Gel filtration
Ultrafiltration
Affinity chromatography
Microfluidic technology		 Biological products accessible only after delivery
Enrichment of EV preparations requires purification steps		 [38][43][44][45]

Table 3. Methods for the detection and confirmation of pregnancy-related EVs.

Detection/Confirmation Techniques Characteristics References
Flow cytometry Not selective enough to analyze membrane and non-membrane structures, as it detects all particles with CD81, CD9, and CD63 markers
It is recommended to use appropriate negative controls (antibodies, isotype controls, etc.)		 [36][37][38][46]
Western blot Most commonly used technique, although not selective enough
Employs the use of STB marker PLAP, as well as exosomal markers Alix and CD63, and potential contaminating markers such as platelet, red blood cell, and leucocyte markers		 [37][38][46]
Fluorescence nanoparticle tracking analysis (fl-NTA) Typically used to determine PLAP-positive EVs, thus reliably identifying STBMV
Facilitates counting, sizing, and phenotyping of EVs		 [47]
Imaging techniques such as electron microscopy, immunoelectron microscopy, scanning electron microscope (SEM), transmission electron microscope (TEM), cryogenic electron microscopy (cryo-EM), scanning probe microscopy (SPM), atomic force microscopy (AFM), super-resolution microscopy (SRM) Used to visualize single EVs at high resolution, providing information on their structure and composition, especially when combined with antibody-mediated detection of EVs components
Allows the detection of exosomal markers directly on the nanovesicle surface
These techniques are not interchangeable as they do not offer information about EVs of comparable characteristics
When dealing with insufficiently purified preparations, co-isolated impurities can lead to misinterpretation of biochemical contents		 [38][48][49][50][51]

While initially regarded as debris, lacking any biological purpose, EVs have over time been demonstrated to play significant roles in intercellular communication, carrying both autocrine and paracrine functions following their secretion [52]. Additionally, due to their immune properties consisting of their behaving as antigen-presenting agents, exosomes especially have been shown to trigger immune responses [53][54]. Moreover, in the central nervous system, EVs have been reported to maintain the myelin coating and promote endogenous brain repair processes, thus making them valuable players in the post stroke recovery period [55][56]. In cancer disease, exosomes released by tumor cells can act as signal transduction mediators while facilitating not only neoplastic development, growth, and metastasis, but also chemoresistance [57][58]. However, above all, the most common interest in the field of EVs probably resides in their potential to serve as biomarkers due to their heterogeneous cargoes unique to specific conditions. To this extent, onco-hematological diseases such as acute myeloid leukemia can be diagnosed by identifying specific mutations in plasma EVs identical to those observed in leukemia cells [59][60]. The use of EVs as biomarkers in disorders of the central nervous system such as Alzheimer’s and Parkinson’s disease has also been reported [61][62], while accumulating evidence points towards a similar use of EVs in coronary artery disease [63][64]. Perhaps the most significant progress has, however, been made in cancer, with clinical trials already on the way, regarding their use as diagnostic tools and/or therapeutic instruments [65][66][67]. Still, more and more data supports the utilization of EVs as biomarkers in pregnancy-related complications, exosome analysis posing advantages such as the accessibility of blood sampling and detection in early pregnancy [11][52][68]. In this regard, a brief exemplification of the multitude of roles that EVs play in both normal and pregnancy-related disorders is summarized in Table 4, and further discussed in the following sections.Table 4. Role of placental EVs during different pregnancy states.

Pregnancy State Role of Placental Extracellular Vesicles
Normal pregnancy Promotion of embryonic implantation and placental development
Maternal immune response modulation
Induction of fetal vasculogenesis
Induction of inflammatory response during parturition
Systemic inflammation Induction of inflammation through altered cargo composition
Increased inclusion of inflammation inducing agents, such as HMG nuclear proteins, TNF-α, GM-CSF, IFN-γ, IL-6, IL-8, miR-155, miR-494, miR-181a, and miR-210
Diminished inclusion of anti-inflammatory agents, such as miR-548c-5p
Gestational hypertension Increased release during PE
Induction of MSIR
Gestational diabetes mellitus Increased release during GDM
Increased inclusion of IR implicated miRNAs, such as hsa-miR-125a-3p, hsa-miR-99b-5p, hsa-miR-197-3p, hsa-miR-22-3p and hsa-miR-224-5p
Differential inclusion of miRNAs, such as miR-16-5p, miR-17-5p, and miR-20a-5p
Viral infections Inclusion of anti-viral agents, such as LC3, UVRAG, ATG4C, and IFN-λ1
Speculated beneficial role for viral spread through immune evasion
Viral sheathing by exosomes
Fetal growth restriction Increased ratio of placental to total exosomes
Increased inclusion of miRNAs, such as miR-942-5p, miR-223-5p, miR-20b-5p, miR-324-3p, and miR-127-3p

2. Extracellular Vesicles in Normal Pregnancy

In physiological pregnancy, EVs and exosomes in particular have time and again been indicated to act as components of the fetal-maternal communication during implantation and placentation [69][70][71], while also modulating the maternal immune response [72][73][74][75], maintaining cellular metabolic homeostasis [76][77][78], promoting fetal vasculogenesis together with maternal uterine vascular adaptation [79][80][81], and preparing the uterus for in the delivery process [82][83].Attached to the wall of the uterus, the placenta constitutes the interface between the mother and fetus in the gestational period, ensuring gas exchange, nutrient and waste transfer, immunoglobulin transport, and hormone secretion. The maternal-fetal communication is possible either through simple or facilitated diffusion, active transport, or by means of EVs [45][84][85]. Through their content, embryonic EVs that are engulfed by specific maternal cells, end up regulating maternal adjustments. Further on, placental EVs aid the vascular changes brought about by the pregnancy, while also reflecting the placental function and fetal growth [86]. Placental-derived EVs distinguish themselves mainly through their positivity for the syncytiotrophoblast (STB) marker placental alkaline phosphatase (PLAP), among other STB-derived EVs (STBEVs) [37][86], while both early and term placental cytotrophoblast cells have been demonstrated to secrete, by means of exosomes, members of the B7 family of immunomodulatory molecules, namely B7-H1 (CD274), B7-H3 (CD276), and human leukocyte antigen-G5 molecules (HLA-G5) [87]. Maternal and fetal exosome transfer in both directions has been demonstrated using fluorescently labeled exosomes in pregnant mouse models, thus reinforcing the isolation of exosomes from maternal blood samples as a non-invasive liquid biopsy [85][88].Similar to other EVs, placenta-derived EVs are abundant in miRNAs, regulators of gene expression at post-transcriptional level, exerting their effects by targeting multiple mRNAs [89]. By these means, miRNAs carried by EVs and transported to specific cells end up modifying the gene expression pattern of the recipient cells. Among placenta-associated miRNAs, 46 miRNAs belonging to the chromosome 19miRNA cluster (C19MC) have been identified, being expressed in villous trophoblasts [90][91]. Among these, miR-517b favors TNFα expression [92], while miR-516b-5p, miR-517-5p, and miR-518a-3p have been shown to impact the PI3K-Akt and the insulin signaling pathways, their expression levels being regulated by various stimuli, including oxidative stress and blood glucose levels [93]. Furthermore, in healthy dairy cow pregnancy models, placental exosome-derived miR-499 has been shown to downregulate NF-κB activation by targeting the Lin28B/let-7-ras signaling axis, therefore maintaining a slight proinflammatory profile [94].

2.1. EVs in Embryo Implantation

Embryo implantation, first in the series of events required for a prosperous pregnancy, is a crucial process necessitating a chain of molecular operations that ultimately accomplish the adhesion of the trophectoderm to the endometrial epithelial cells [95][96]. While mediators such as adhesion molecules, growth factors, hormones, and cytokines are known as crucial for endometrial receptivity, EVs have more recently been shown to aid the implantation process [97][98][99]. To this extent, it has been proposed and reported that endometrium-derived EVs are assimilated and internalized by both trophoblasts and surrounding endometrial cells, eventually enhancing their adhesive capacity, especially by means of gene expression modulation due to their content in miRNA [100]. In this regard, Ng YH, and colleagues have analyzed a panel of 227 endometrial exosomal miRNAs and showed that numerous of their target genes were in fact crucial for implantation, since they were responsible for regulating not only essential pathways, such as the VEGF pathway, the Toll-like receptor pathway and the Jak-STAT pathway, but also extracellular matrix (ECM)-receptor interactions and adherens junctions [100]. On the same note, Vilella et al. have shown that endometrium exosome-derived hsa-miR-30d, when taken up by trophoblasts, enhances the gene expression of Integrin Subunit Alpha 7 (Itg7), Integrin Subunit Beta-3 (Itgb3), and Cadherin 5 (Cdh5) proteins, all three required for blastocyst implantation [101], while Greening and colleagues have later demonstrated that endometrial EVs, when internalized by the trophectoderm, augment their adhesiveness via the focal adhesion kinase (FAK) signaling pathway [102].

2.2. EVs in Spiral Artery Remodeling

Following successful implantation, decidualization and placentation take place, the resulting placenta ensuring the necessary resources for the optimal development of the embryo [103]. The nutrient supply is facilitated by the uterine spiral arteries, which go through substantial transformation under the influence of adaptive mechanisms carried out by cellular and molecular factors [104]. Specifically, both cellular and extracellular components of the maternal uterine spiral arteries undergo modifications such as apoptosis, hyperplasia and hypertrophy, migration, and ECM remodeling, all under the rigorous coordination of invasive cytotrophoblast cells and decidual natural killer (NK) cells [105]. Trophoblast cells end up replacing the distal endothelial cells, acquiring a low-resistance vascular bed phenotype, fitting for unrestricted blood flow [106]. During placental development, the migration of vascular smooth muscle cells (VSMC) plays a key role in spiral artery remodeling, a movement which has been demonstrated to be in part promoted by EVs released by extravillous trophoblast (EVT) cells via a novel EVT-VSMC exosomal communication pathway [107]. Furthermore, exosomal miRNAs together with vascular endothelial growth factor A (VEGFA) have been reported to be discharged by the implanted embryo, so as to adjust blood flow [79][108]. Dependent upon oxygen levels, placental EVs have also been reported to stimulate vasculo-angiogenesis, especially in hypoxic conditions [71]. On the same note, Jia and colleagues have researched the role of maternal and umbilical cord blood exosomes on angiogenesis. By analyzing healthy pregnant women, they found that both maternal and umbilical exosomes promoted human umbilical vein endothelial cells (HUVEC) proliferation and migration, along with angiogenesis, with 258 miRNAs being upregulated in both types of exosomes [80]. Other trophoblast cells derived-EVs that have also been reported to have pro-angiogenic effects by enhancing the proliferation of maternal endothelial cells via particular angiogenesis-related miRNA regulation have been identified in umbilical cord blood [109].

2.3. EVs in Parturition

Provided that the course of pregnancy is not impaired, delivery is set to take place following fetal maturation, as a result of a parturition cascade involving proinflammatory events that ultimately trigger labor [110]. Still, the precise mechanism that leads to the initiation of the delivery process has not been completely elucidated, but EVs are thought to act as mediators that, mainly due to their content rich in complex molecules, end up reprogramming the phenotype of surrounding cells, eventually regulating their function [111]. In this regard, Menon and colleagues have analyzed placental EVs during pregnancy and at delivery, and found that samples at term associated a group of upregulated genes known to be regulators of epithelial mesenchymal transition (EMT). They hypothesized that, when approaching term, fetal components of the placenta undergo EMT, which leads to an increase in mesenchymal cells susceptible to oxidative stress followed by subsequent inflammation that precipitates delivery [112][113]. Moreover, as a response to increased oxidative stress, it has been demonstrated that phosphorylation of p38 mitogen-activated protein kinase (MAPK), an indicator of term parturition, takes place in amniotic epithelial cell (AEC)-derived exosomes [114]. Along the same lines, Hadley et al. later investigated whether oxidative stress prompted the production of exosomes by AEC, and found that indeed AEC undergoing oxidative stress released around seven times more exosomes than control cells, which, in turn, lead to the activation of the NF-κβ protein complex along with an increase in PGE2, IL-6, and IL-8 in endometrial and myometrial cells [115]. On a similar note, Sheller-Miller et al. have revealed that, predictably, maternal plasma EV concentration enhanced with gestational age, while EVs rich in particles promoting inflammation—e.g., plasminogen (PLG), catalase, TNF-α— were dominant ahead of parturition [82].

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Panagiotis Antoniadis
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