JARB Journal of Animal Reproduction and Biotehnology

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Journal of Animal Reproduction and Biotechnology 2022; 37(1): 2-12

Published online March 31, 2022

https://doi.org/10.12750/JARB.37.1.2

Copyright © The Korean Society of Animal Reproduction and Biotechnology.

The theranostic roles of extracellular vesicles in pregnancy disorders

Islam M. Saadeldin1,2,3 , Bereket Molla Tanga1 , Seonggyu Bang1 , Xun Fang1 , Ki-Young Yoon4 , Sanghoon Lee1 and Jongki Cho1,*

1Lab. of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
2Research Institute of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
3Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
4Department of Companion Animal, Shingu College, Seongnam 13174, Korea

Correspondence to: Jongki Cho
E-mail: cjki@cnu.ac.kr

Received: November 10, 2021; Revised: December 1, 2021; Accepted: December 1, 2021

Extracellular vesicles (EVs) are nanovesicles that carry bioactive cargoes of proteins, lipids, mRNAs, and miRNAs between living cells. Their role in cellular communication has gained the attention of several research reports globally in the last decade. EVs are critically involved in sperm functions, oocyte functions, fertilization, embryonic development, and pregnancy. The review summarizes the state-of-the-art of EVs research in the diagnostic and therapeutic (theranostic) potentials of the EVs during the pregnancy that might provide a solution for gestational disturbances such as implantation failure, maternal health problems, gestational diabetes, and preeclampsia. EVs can be found in all biological fluids of the fetus and the mother and would provide a non-invasive and excellent tool for diagnostic purposes. Moreover, we provide the current efforts in manufacturing and designing targeted therapeutics using synthetic and semi-synthetic nanovesicles mimicking the natural EVs for efficient drug delivery during pregnancy.

Keywords: diagnosis, extracellular vesicles, placenta, pregnancy, therapy

Extracellular vesicles (EVs) are group of nanovesicles secreted by living cells and their diameter range from 30 nm up to 1 ?m. They include exosomes, microvesicles, ectosomes, and apoptotic bodies (Zhang et al., 2019b). EVs carry nucleic acid and protein cargo, are secreted by many types of cells to help in cell-to-cell communication and play an important crucial role in reproduction physiology (Qamar et al., 2020; Fang et al., 2021; Qamar et al., 2021; Saadeldin, 2021).

The generic term EVs is used to describe all secreted membrane vesicles. The International Society for Extracellular Vesicles (ISEV) has defined and categorized EVs into three main groups: apoptotic bodies; microvesicles; and nanosized EVs called exosomes (Crescitelli et al., 2013; Th?ry et al., 2018; Willms et al., 2018). EVs can transfer messenger RNA, micro-RNA (miRNA), proteins, and lipids cargoes in between different cells, alter gene expression, and modulate the target cells behaviors (Deregibus et al., 2007; Crescitelli et al., 2013; Raposo and Stoorvogel, 2013; Colombo et al., 2014; Kowal et al., 2014; Lo Cicero et al., 2015; Th?ry et al., 2018). EVs can be defined by specific tetraspanins or surface markers such as CD9, CD63, and CD81 (Fig. 1) (Colombo et al., 2014).

Figure 1. The diagnostic roles of extracellular vesicles (EVs) derived from different stages of pregnancy. EVs express tetraspanins such as CD9, CD63, and CD81. EVs interplay during embryo implantation, secreted in all biological fluids (amniotic fluid and blood) of the fetus and maternal circulation, and can be a marker for placental functions. Isolating and charactering EVs would be a helpful tool to diagnose and monitor gestational pathophysiology such as maternal health, embryo growth, gestational diabetes, and preeclampsia.

Exosomes (30-180 nm diameter) are biosynthesized in the multivesicular bodies (MVBs) and require sorting of contents before exosomes secretion via endocytic pathway (van Niel et al., 2018). Their shapes are rounded or cup-shaped vesicles and can carry proteins, ribonucleic acids (RNAs), and lipids (Zhang et al., 2019b). Microvesicles (100-1000 nm diameter) are resulted from cell membrane budding and fissions, and of different shapes. Unlike the exosomes and microvesicles, apoptotic bodies are ranging from 500-2000 nm and resulted from endoplasmic reticulum and cell membrane, and contain nuclear factions and deoxyribonucleic acid (DNA) (Alharbi et al., 2021).

Theranostics is a term integrating the translational research of diagnosis, prognosis, and therapeutics, and provides a transition from conventional way of medicine to a targeted and personalized medicine. The involvement of EVs in all stages of mammalian reproduction including males, females, fertilization, embryonic development, and pregnancy has attracted many researchers to unveil the potential roles in diagnosis and therapy of several reproductive disorders (Saadeldin et al., 2014; Saadeldin et al., 2015; Mahiddine et al., 2020; Abdelaal et al., 2021; Qamar et al., 2021). Moreover, easiness in retrieval allows scientist to use EVs as a non-invasive tool to judge on the embryo quality and pregnancy in contrary to the invasive tools (Ali et al., 2020; Cho et al., 2020). In this review, we highlighted the important theranostic roles of EVs during the entire stages of pregnancy started from implantation, placentation, and fetal growth.

Role of EVs in implantation and pregnancy

1) EVs and embryo adhesion to endmoetrium

The roles of EVs and exosomes are claimed to be the markers in reproduction but it is beyond the marker; they paly pivotal role, particularly evidenced in pig for establishing successful pregnancy (Jankovi?ov? et al., 2020). The efficiency of in vivo as compared to that of the in vitro in claimed to be due to the lack of maternal and embryo communication, mainly through cargo’s transferred between embryo and mother (Betteridge, 2003; De Bem et al., 2017; Jankovi?ov? et al., 2020).

Some reports indicate that EVs, particular exosome-like vesicles, found to express putative endometrial markers, such as glycodelin A and receptors for estrogen and progesterone, thus confirming their endometrial origin (Luddi et al., 2019). The flushing of uterine has yielded EVs, found to be the richest source of endometrial transcripts and showed endometrial gene profiles (Luddi et al., 2019). EVs can cross the physiological barriers, and essential roles in cell-to-cell communication (Nair and Salomon, 2018).

EVs showed role in embryo attachment to the endometrium during maternal recognition of pregnancy, evidenced in most of domestic animals where serum EVs contain specific miRNAs that target the focal adhesion (FA) signals, mainly through decreasing the prostaglandin F secretion (Klohonatz et al., 2019). The source of the EVs leads to the variation in the functions, for instance macrophage derived EVs were found to induce placental pro-inflammatory responses, but those originated from monocytes did not affect pro-inflammatory responses (Rice et al., 2018). Similarly, the macrophage originated exosomes were found to induce placental inflammatory cytokines, as a means of mode of the control of the maternal embryo communication (Holder et al., 2016).

The serum EVs in mares contain miRNAs that change upon pregnancy status and may modulate mRNA expression related to embryo adhesion to the endometrium. This data indicates that the exosomes is playing roles in having different cargoes for various physiological state (Klohonatz et al., 2016), which may an indication of a potential role in maternal recognition of pregnancy. Moreover, plasma miRNA has been used also to early monitor the pregnancy in cattle (Lim et al., 2021). Furthermore, the endometrial derived exosomes previously described were identified from uterine flushing, found to modulate endometrial response, which suggest that EVs secreted from embryos and endometrium are involved in embryonic-maternal interactions for successful conceptus implantation (Nakamura et al., 2016).

In humans also, exosomes were internalized by trophoblast cells and showed to enhance the adhesive capacity, a response mediated partially through active focal adhesion kinase signaling. Thus, exosomes found to contribute to the endometrial-embryo interactions within the human uterine microenvironment essential for successful implantation (Greening et al., 2016). The analysis of endometrial fluid has also revealed there were cytokines, chemokines, proteases, antiproteases and other factors, which could have capacity to modulate blastocyst and functions for the implantation (Salamonsen et al., 2016). EVs released from the early developing embryos and the endometrium are found in the uterine fluid and function to transfer mRNAs, miRNAs, proteins, and lipids between cells during the peri-implantation period (Salamonsen et al., 2016; Nakamura et al., 2020).

2) EVs and endometrium immunomodulation

EVs are a critical modulator of immunological response in the physiological and pathological conditions, and pregnancy is a complicated interaction of immune system protects the early embryo and fetus from immunological rejection to maintain successful pregnancy till full-term and delivery (Nair and Salomon, 2018). As placenta play a vital role in performing a multitude of functions to support the pregnancy, and it found to contain EVs that regulating the maternal immune response for successful pregnancy establishment and outcome (Tannetta et al., 2014; Nair and Salomon, 2018). Placenta-derived EVs show several functions such as suppressing immune reactions to the developing embryos, establishing and maintaining a regulatory inflammatory response to combat microbial and pathogenic attacks (Tannetta et al., 2014). Adjustment of these mechanisms is crucial for successful gestation and healthy progeny. Alterations in these mechanisms will ultimately lead to pregnancy complications and disorders (Nair and Salomon, 2018).

Furthermore, the preimplantation embryo-derived EVs carry certain cargoes potentially capable of modulating the endometrial immune response (Giacomini et al., 2019), which is believed to be basic functional change expected on embryo maternal immune scape mechanism (Trowsdale and Betz, 2006). In other ways, EVs exert a paradoxical and temporal immunotolerance and proinflammatory effects during fertilization, and subsequent implantation, respectively (Trowsdale and Betz, 2006).

EVs from amniotic fluid also showed the immunomodulation function and able to affect the essential molecules in immunity like transforming growth factor beta and hepatic growth factors (Beretti et al., 2018). The EVs effect was also observed on peripheral blood mononuclear cells, which indicates that it can modify the inflammatory response (Admyre et al., 2007).

The roles of exosomes are also extended to contain bioactive Fas-L and TRAIL, which are able to induce apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its EVs secretions (Stenqvist et al., 2013). And its immunoregulatory roles extend to the late pregnancy stage, observed on a third trimester normal pregnant women, producing TNFα and IL-6, confirming that maternal immune cells are primed by pregnancy, which functions regulated by exosome communication in paternal-paternal crosstalk (Southcombe et al., 2011).

Diagnostic roles for female infertility and pregnancy disorders

Interestingly, placental cells such as trophoblasts and syncytiotrophoblasts release EVs as early as the pregnancy established and the release is modulated by the health condition of the pregnancy and the placenta, such as the oxygen tension, circulation, and glucose (Ouyang et al., 2014; Albrecht et al., 2016; Mobarak et al., 2019a; Mobarak et al., 2019b). Importantly, the amniotic fluid represents an enriched source of diagnostic biomarkers of abundant maternal and fetal nucleic acid and proteins carried on the EVs cargo and reflect the maternal and fetal health status (Ebert and Rai, 2019). We summarize the diagnostic potentials of EVs during pregnancy to monitor both maternal and fetal pathophysiology (Fig. 1).

1) Mother health

Analysis of exosomal contents could provide a non-invasive tool for detecting the maternal health during pregnancy. For instance, the relative concentration and numbers of exosomes are increased in the maternal circulation of obese pregnant women that is mostly related to the increased lipid levels, inflammatory reactions, hyperglycemia and oxidative stress, as indicated by increase in the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor (TNF-α) (Salomon et al., 2013; Rice et al., 2015; Elfeky et al., 2017; Delhaes et al., 2018). Notably, the placental EVs miRNA signature (particularly mir-517A and mir-518B) is markedly correlated with the conditions of the placenta (Luo et al., 2009). These miRNAs showed dramatic decrease after the delivery that clearly indicated about the placental functionality during pregnancy (Luo et al., 2009). Interestingly, amniotic fluid EVs reflect the oxidative stress status of the embryonic cells. Additionally, the high-mobility group box 1 (HMGB1) and cell-free fetal telomere fragments (cffTF) contents in the amniotic fluid EVs were all increased in the damaged and senescence-induced oxidative stressed amniotic epithelial cells (Sheller-Miller et al., 2017). Amnion epithelial cells EVs characteristics, heat shock protein (HSP) 70 contents, and the activated form of pro-senescence and term parturition associated marker p38 mitogen activated protein kinase (MAPK) (P-p38 MAPK) were all elevated after exposure to oxidative stress (Sheller et al., 2016). Furthermore, maternal exposure to alcohol alters the amniotic fluid EVs miRNA contents (upregulated let-7g, 25-3p, 199a-3p and 214-3p and downregulated 206-3p and 22-3p) and showed significant molecular effects on stem cell regulation and differentiation (Tavanasefat et al., 2020).

2) Genetic diseases

In the last few years, studies have explained that large sized EVs contain packaged DNA molecules and could be released from fetal origins (Hahn et al., 2014; Repisk? et al., 2018; Kone?n? et al., 2019). Therefore, plasma cell-free or exosomal DNA can be a marker for the genetic diseases and follow up of the pregnancy complications till term and delivery (Kone?n? et al., 2019). Interestingly, the DNA-associated micro-particles (MPs) in maternal plasma express fetal-derived human leukocyte antigen-G (HLA-G) or placental alkaline phosphatase (PLAP) are increased in the second trimester of pregnant women and further increased in pre-eclampsia patients (Orozco et al., 2009). Another form of the EVs, the apoptotic nanoparticles enriched with stable DNA strands, was significantly increased in the pregnancy complications such as pre-eclampsia (Orozco et al., 2008).

3) Early embryo and Fetal growth

EVs could play an important marker for the monitoring of embryonic growth and health status (Yang et al., 2020). The concentrations of placental EVs (positive for placental alkaline phosphatase/CD63) were significantly reduced in case of fetal growth restriction (FGR) (Miranda et al., 2018).

Furthermore, the EVs contents of miR-20b-5p, miR-942-5p, miR-324-3p, miR-223-5p, and miR-127-3p were increased in the maternal serum of small-for-gestational ages infants, while miR-661, miR-212-3p, and miR-197-3p were elevated in the maternal serum of large-for-gestational age infants (Rodosthenous et al., 2017). Moreover, there was a correlation between the levels of miRNAs (miR-483-5p, miR-10a-5p, miR-204-5p, miR-202-3p, miR-345-5p, miR-885-5p, miR-127-3p, miR-148b-3p, miR-324-3p, miR-1290, miR-597-5p, miR-139-5p, miR-215-5p, and miR-99b-5p) and the birth weight-for-gestational age z-score as non-invasive biomarkers of monitoring the fetal growth during pregnancy (Rodosthenous et al., 2017).

Interestingly, deep sequencing studies revealed that the EVs contents of miR-25, miR-16b, and miR-3596 were significantly increased in case of early embryonic-mortality on day-17 and day-24 of pregnancy in cattle (Pohler et al., 2017).

The numbers of placenta derived-EVs in the maternal plasma were dramatically increased with the gestational age (i.e., third trimester vs. second trimester vs. first trimester) and these EVs were able to improve the endothelial cell migration as a step forward to healthy circulation during placentation (Salomon et al., 2014).

Proteomic contents of amniotic fluid EVs of placental alkaline phosphatase/CD63 markers are increased in the normal term labor (TL), spontaneous preterm birth (PTB), and preterm premature rupture of membranes (pPROM) when compared with term not in labor (TNIL). The amniotic fluid EVs were also increased in PTB compared with pPROM (Dixon et al., 2018). Amniotic fluid EVs concentrations were also positively correlated with the number of pregnancies and the HSP contents were increased by the mid-trimester and may contribute to immune regulation within the amniotic cavity (Asea et al., 2008).

4) Gestational diabetes

One of the problems associated with pregnant women in the last trimester is the insulin resistance and gestational diabetes mellitus (GDM) and its complications such as foetoplacental endothelial dysfunction (S?ez et al., 2018a). Using the EVs is a promising tool for GDM diagnosis, follow up, and appropriate interference with the affected pregnant women. The concentration of circulating EVs is proportionally correlated with the gestational age and physical condition of the pregnant women and the concentration was increased more significantly in case of GDM (Salomon et al., 2016; Liu et al., 2018). Sequencing data of EVs from GDM affected women showed variable expression of certain miRNAs, such as hsa-miR-125a-3p, hsa334 miR-99b-5p, hsa-miR-197-3p, hsa-miR-22-3p and hsa-miR-224-5p that are linked to PI3/AKT signaling and glucose metabolism/insulin resistance (Nair et al., 2018). Interestingly, EVs were isolated from the human umbilical vein endothelium of normal and GDM-affected women and supplemented to the endothelium. EVs from GDM showed delayed wound healing for the endothelium when compared with the normal EVs. Moreover, EVs of GDM increased L-arginine transport, hCAT-1 and eNOS expression and activity, reactive oxygen species, and p44/42mapk activation in the endothelium (S?ez et al., 2018b).

5) Preeclampsia and placenta dysfunction (preterm labor)

Preeclampsia is a pregnancy disorder clinically recognized by increased systolic blood pressure and symptoms of liver and kidney damages. Preeclampsia often appears on the 20th weeks of pregnant women whose blood pressure had been normal (Roberts and Cooper, 2001). Several research groups unraveled the essential diagnostic roles of the EVs as well as the mediation of preeclampsia pathogenesis and other placental disorders (van der Post et al., 2011; Mitchell et al., 2015; Tsochandaridis et al., 2015; Gilani et al., 2016; Cuffe et al., 2017; Ermini et al., 2017; Pillay et al., 2017; Salomon and Rice, 2017; Tannetta et al., 2017a; Tannetta et al., 2017b; Jin and Menon, 2018; Morgan, 2018; Salomon et al., 2018).

It has been found that the relative concentration of placental-derived EVs increased in early onset preeclampsia but decreased in late onset preeclampsia compared to the normal pregnancy. The ratio of PLAP+ EVs/total number of EVs was reduced in early onset preeclampsia and late onset preeclampsia (Pillay et al., 2016). It has been reported that the placental protein 13 (PP13) was reduced in placental derived syncytiotrophoblast extracellular vesicles in preeclampsia suggesting its pathophysiological role in the maternal circulation (Sammar et al., 2018).

Syncytiotrophoblast EVs were increased in numbers and showed altered molecular loads and modulated the exaggerated inflammatory state during preeclampsia (G?hner et al., 2017). Furthermore, higher levels of neprilysin have been identified in preeclampsia EVs that possesses a pathological role in preeclampsia-associated hypertension, heart failure, and amyloid deposition (Gill et al., 2019).

Interestingly, miR-141 expression was increased in the placentae from preeclampsia patients and its inhibition in trophoblasts decreased cellular viability and invasion capabilities (Ospina-Prieto et al., 2016). Additionally, the level of circulating exosomal hsa-miR-210 was increased in preeclampsia placentas (Bir? et al., 2019). It is known that hsa-miR-210 significantly impacts the cellular viability, metabolic activity, and invasion capability of trophoblasts (Muralimanoharan et al., 2012; Luo et al., 2016; Hayder et al., 2021). Moreover, syncytin-2 was found to be reduced in serum-derived EVs from women with preeclampsia when compared to the normal pregnancy (Vargas et al., 2014).

The concentration of EVs was increased in extravillous trophoblast cultured under 1% compared to 8% O2. Moreover, hundreds of miRNAs were identified in extravillous trophoblast EVs and were associated with cellular migration and cytokine generation. Furthermore, EVs from extravillous trophoblast cultured at 8% O2 increased the endothelial cells migration when compared with those cultured at 1% O2 (Truong et al., 2017).

Pre-term birth is another problem associated with placental dysfunctions and can lead to lifelong complications of the pre-term born babies. Several miRNAs have been identified in the EVs of the preterm births that could be a useful biomarker for predicting the pre-term birth. Results revealed that hsa-miR-100-5p, hsa-miR-141-3p, hsa-miR-194-5p, hsa-miR-515-5p, hsa-miR-517a-3p, hsa-miR518e-5p, hsa-miR-525-5p, hsa-miR-377-3p, and hsa-miR-483-5p are good candidates for predicting pre-term birth when analyzed in the EVs isolated from the maternal plasma (Fallen et al., 2018).

Therapeutic roles of synthetic and semi-synthetic exosomes for female infertility and pregnancy

Based on the previously mentioned roles of EVs for pathogenesis and diagnosis of pregnancy disorders, the necessity for therapeutic interventions is needed. The EVs as a drug delivery option showed several advantages. First, EVs is extracted from the patient’s own cells, and hence they are less immunogenic. Second, EVs contain lipid bilayers where they increase the cellular internalization of loaded drugs. Third, the minute size of EVs avoids the phagocytosis by immune cells. In addition, EVs showed specificity for fusion with the target cells and therefore would reduce off-target effects (Zhang et al., 2019b). Nanotechnology and nanomedicine have introduced encouraging results for the development of novel targeted delivery of drugs during the pregnancy (Zhang et al., 2019a; Hashem and Gonzalez-Bulnes, 2020; Pereira et al., 2020). Surface-functionalized plCSA binding peptide (plCSA-BP)-decorated nanoparticles could be successfully designed to target placental chondroitin sulfate A that uniquely expressed in the placenta (Zhang et al., 2019a). Similar surface-functionalized nanoparticles, liposomes, immunoliposomes, or the lipid-polymer nanoparticles and their target drug delivery for uterus and placenta to treat pre-term birth, ectopic pregnancy, and fetal growth restriction are reviewed in (Zhang et al., 2019a).

Peptide-bound liposomes are mimicking the functions of EVs and also have been used for the targeted drug delivery for pregnancy complications (Pepe and Albrecht, 2021). For instance, intravenous injection of liposomes containing the peptide CRGDKGPDC bound to insulin-like growth factor (IGF-2) enhanced placental weight in wild type animals (King et al., 2016). Similarly, miRNA can be loaded in the liposomes and used for therapeutics during pregnancy. Liposomes were decorated with the peptide CCGKRK and bound with miR-145 or miR-675 inhibitor peptide nucleic acid conjugate to suppress miR-145 or miR-675, respectively. These liposomes were injected in the pregnant mice and increased the fetal and placental weights and enhanced the human cytotrophoblast proliferation in vitro (Beards et al., 2017).

Overall, re-engineering placenta-specific EVs is a very promising approach for the development of bio-inspired and targeted drug delivery systems to treat pregnancy complications (Du et al., 2017; Arrighetti et al., 2019).

There is a trending and encouraging data that support the potential diagnostic and therapeutic roles of EVs during the early stages of embryonic development, fetal development, and maternal health. Investigating the molecular cargo of the EVs provides a non-invasive tool for diagnostics of critical illness of the fetus and mother, and guides for natural and synthetic targeted EVs-like therapeutics.

Conceptualization, I.M.S, and J.C.; writing?original draft preparation, I.M.S, B.M.T., S.B., X.F., K.Y., S.L., and J.C.; writing?review and editing, I.M.S, B.M.T., S.B., X.F., K.Y., S.L., and J.C.; supervision, J.C.; project administration, J.C.; funding acquisition, J.C.

This work was supported by the Ministry of Science and ICT through the National Research Foundation of Korea (NRF) (grant No. 2021R1A2C2009294) and the Brain Pool program (grant No.: 2021H1D3A2A02040098).

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Article

Review Article

Journal of Animal Reproduction and Biotechnology 2022; 37(1): 2-12

Published online March 31, 2022 https://doi.org/10.12750/JARB.37.1.2

Copyright © The Korean Society of Animal Reproduction and Biotechnology.

The theranostic roles of extracellular vesicles in pregnancy disorders

Islam M. Saadeldin1,2,3 , Bereket Molla Tanga1 , Seonggyu Bang1 , Xun Fang1 , Ki-Young Yoon4 , Sanghoon Lee1 and Jongki Cho1,*

1Lab. of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
2Research Institute of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea
3Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
4Department of Companion Animal, Shingu College, Seongnam 13174, Korea

Correspondence to:Jongki Cho
E-mail: cjki@cnu.ac.kr

Received: November 10, 2021; Revised: December 1, 2021; Accepted: December 1, 2021

Abstract

Extracellular vesicles (EVs) are nanovesicles that carry bioactive cargoes of proteins, lipids, mRNAs, and miRNAs between living cells. Their role in cellular communication has gained the attention of several research reports globally in the last decade. EVs are critically involved in sperm functions, oocyte functions, fertilization, embryonic development, and pregnancy. The review summarizes the state-of-the-art of EVs research in the diagnostic and therapeutic (theranostic) potentials of the EVs during the pregnancy that might provide a solution for gestational disturbances such as implantation failure, maternal health problems, gestational diabetes, and preeclampsia. EVs can be found in all biological fluids of the fetus and the mother and would provide a non-invasive and excellent tool for diagnostic purposes. Moreover, we provide the current efforts in manufacturing and designing targeted therapeutics using synthetic and semi-synthetic nanovesicles mimicking the natural EVs for efficient drug delivery during pregnancy.

Keywords: diagnosis, extracellular vesicles, placenta, pregnancy, therapy

INTRODUCTION

Extracellular vesicles (EVs) are group of nanovesicles secreted by living cells and their diameter range from 30 nm up to 1 ?m. They include exosomes, microvesicles, ectosomes, and apoptotic bodies (Zhang et al., 2019b). EVs carry nucleic acid and protein cargo, are secreted by many types of cells to help in cell-to-cell communication and play an important crucial role in reproduction physiology (Qamar et al., 2020; Fang et al., 2021; Qamar et al., 2021; Saadeldin, 2021).

The generic term EVs is used to describe all secreted membrane vesicles. The International Society for Extracellular Vesicles (ISEV) has defined and categorized EVs into three main groups: apoptotic bodies; microvesicles; and nanosized EVs called exosomes (Crescitelli et al., 2013; Th?ry et al., 2018; Willms et al., 2018). EVs can transfer messenger RNA, micro-RNA (miRNA), proteins, and lipids cargoes in between different cells, alter gene expression, and modulate the target cells behaviors (Deregibus et al., 2007; Crescitelli et al., 2013; Raposo and Stoorvogel, 2013; Colombo et al., 2014; Kowal et al., 2014; Lo Cicero et al., 2015; Th?ry et al., 2018). EVs can be defined by specific tetraspanins or surface markers such as CD9, CD63, and CD81 (Fig. 1) (Colombo et al., 2014).

Figure 1.The diagnostic roles of extracellular vesicles (EVs) derived from different stages of pregnancy. EVs express tetraspanins such as CD9, CD63, and CD81. EVs interplay during embryo implantation, secreted in all biological fluids (amniotic fluid and blood) of the fetus and maternal circulation, and can be a marker for placental functions. Isolating and charactering EVs would be a helpful tool to diagnose and monitor gestational pathophysiology such as maternal health, embryo growth, gestational diabetes, and preeclampsia.

Exosomes (30-180 nm diameter) are biosynthesized in the multivesicular bodies (MVBs) and require sorting of contents before exosomes secretion via endocytic pathway (van Niel et al., 2018). Their shapes are rounded or cup-shaped vesicles and can carry proteins, ribonucleic acids (RNAs), and lipids (Zhang et al., 2019b). Microvesicles (100-1000 nm diameter) are resulted from cell membrane budding and fissions, and of different shapes. Unlike the exosomes and microvesicles, apoptotic bodies are ranging from 500-2000 nm and resulted from endoplasmic reticulum and cell membrane, and contain nuclear factions and deoxyribonucleic acid (DNA) (Alharbi et al., 2021).

Theranostics is a term integrating the translational research of diagnosis, prognosis, and therapeutics, and provides a transition from conventional way of medicine to a targeted and personalized medicine. The involvement of EVs in all stages of mammalian reproduction including males, females, fertilization, embryonic development, and pregnancy has attracted many researchers to unveil the potential roles in diagnosis and therapy of several reproductive disorders (Saadeldin et al., 2014; Saadeldin et al., 2015; Mahiddine et al., 2020; Abdelaal et al., 2021; Qamar et al., 2021). Moreover, easiness in retrieval allows scientist to use EVs as a non-invasive tool to judge on the embryo quality and pregnancy in contrary to the invasive tools (Ali et al., 2020; Cho et al., 2020). In this review, we highlighted the important theranostic roles of EVs during the entire stages of pregnancy started from implantation, placentation, and fetal growth.

Role of EVs in implantation and pregnancy

1) EVs and embryo adhesion to endmoetrium

The roles of EVs and exosomes are claimed to be the markers in reproduction but it is beyond the marker; they paly pivotal role, particularly evidenced in pig for establishing successful pregnancy (Jankovi?ov? et al., 2020). The efficiency of in vivo as compared to that of the in vitro in claimed to be due to the lack of maternal and embryo communication, mainly through cargo’s transferred between embryo and mother (Betteridge, 2003; De Bem et al., 2017; Jankovi?ov? et al., 2020).

Some reports indicate that EVs, particular exosome-like vesicles, found to express putative endometrial markers, such as glycodelin A and receptors for estrogen and progesterone, thus confirming their endometrial origin (Luddi et al., 2019). The flushing of uterine has yielded EVs, found to be the richest source of endometrial transcripts and showed endometrial gene profiles (Luddi et al., 2019). EVs can cross the physiological barriers, and essential roles in cell-to-cell communication (Nair and Salomon, 2018).

EVs showed role in embryo attachment to the endometrium during maternal recognition of pregnancy, evidenced in most of domestic animals where serum EVs contain specific miRNAs that target the focal adhesion (FA) signals, mainly through decreasing the prostaglandin F secretion (Klohonatz et al., 2019). The source of the EVs leads to the variation in the functions, for instance macrophage derived EVs were found to induce placental pro-inflammatory responses, but those originated from monocytes did not affect pro-inflammatory responses (Rice et al., 2018). Similarly, the macrophage originated exosomes were found to induce placental inflammatory cytokines, as a means of mode of the control of the maternal embryo communication (Holder et al., 2016).

The serum EVs in mares contain miRNAs that change upon pregnancy status and may modulate mRNA expression related to embryo adhesion to the endometrium. This data indicates that the exosomes is playing roles in having different cargoes for various physiological state (Klohonatz et al., 2016), which may an indication of a potential role in maternal recognition of pregnancy. Moreover, plasma miRNA has been used also to early monitor the pregnancy in cattle (Lim et al., 2021). Furthermore, the endometrial derived exosomes previously described were identified from uterine flushing, found to modulate endometrial response, which suggest that EVs secreted from embryos and endometrium are involved in embryonic-maternal interactions for successful conceptus implantation (Nakamura et al., 2016).

In humans also, exosomes were internalized by trophoblast cells and showed to enhance the adhesive capacity, a response mediated partially through active focal adhesion kinase signaling. Thus, exosomes found to contribute to the endometrial-embryo interactions within the human uterine microenvironment essential for successful implantation (Greening et al., 2016). The analysis of endometrial fluid has also revealed there were cytokines, chemokines, proteases, antiproteases and other factors, which could have capacity to modulate blastocyst and functions for the implantation (Salamonsen et al., 2016). EVs released from the early developing embryos and the endometrium are found in the uterine fluid and function to transfer mRNAs, miRNAs, proteins, and lipids between cells during the peri-implantation period (Salamonsen et al., 2016; Nakamura et al., 2020).

2) EVs and endometrium immunomodulation

EVs are a critical modulator of immunological response in the physiological and pathological conditions, and pregnancy is a complicated interaction of immune system protects the early embryo and fetus from immunological rejection to maintain successful pregnancy till full-term and delivery (Nair and Salomon, 2018). As placenta play a vital role in performing a multitude of functions to support the pregnancy, and it found to contain EVs that regulating the maternal immune response for successful pregnancy establishment and outcome (Tannetta et al., 2014; Nair and Salomon, 2018). Placenta-derived EVs show several functions such as suppressing immune reactions to the developing embryos, establishing and maintaining a regulatory inflammatory response to combat microbial and pathogenic attacks (Tannetta et al., 2014). Adjustment of these mechanisms is crucial for successful gestation and healthy progeny. Alterations in these mechanisms will ultimately lead to pregnancy complications and disorders (Nair and Salomon, 2018).

Furthermore, the preimplantation embryo-derived EVs carry certain cargoes potentially capable of modulating the endometrial immune response (Giacomini et al., 2019), which is believed to be basic functional change expected on embryo maternal immune scape mechanism (Trowsdale and Betz, 2006). In other ways, EVs exert a paradoxical and temporal immunotolerance and proinflammatory effects during fertilization, and subsequent implantation, respectively (Trowsdale and Betz, 2006).

EVs from amniotic fluid also showed the immunomodulation function and able to affect the essential molecules in immunity like transforming growth factor beta and hepatic growth factors (Beretti et al., 2018). The EVs effect was also observed on peripheral blood mononuclear cells, which indicates that it can modify the inflammatory response (Admyre et al., 2007).

The roles of exosomes are also extended to contain bioactive Fas-L and TRAIL, which are able to induce apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its EVs secretions (Stenqvist et al., 2013). And its immunoregulatory roles extend to the late pregnancy stage, observed on a third trimester normal pregnant women, producing TNFα and IL-6, confirming that maternal immune cells are primed by pregnancy, which functions regulated by exosome communication in paternal-paternal crosstalk (Southcombe et al., 2011).

Diagnostic roles for female infertility and pregnancy disorders

Interestingly, placental cells such as trophoblasts and syncytiotrophoblasts release EVs as early as the pregnancy established and the release is modulated by the health condition of the pregnancy and the placenta, such as the oxygen tension, circulation, and glucose (Ouyang et al., 2014; Albrecht et al., 2016; Mobarak et al., 2019a; Mobarak et al., 2019b). Importantly, the amniotic fluid represents an enriched source of diagnostic biomarkers of abundant maternal and fetal nucleic acid and proteins carried on the EVs cargo and reflect the maternal and fetal health status (Ebert and Rai, 2019). We summarize the diagnostic potentials of EVs during pregnancy to monitor both maternal and fetal pathophysiology (Fig. 1).

1) Mother health

Analysis of exosomal contents could provide a non-invasive tool for detecting the maternal health during pregnancy. For instance, the relative concentration and numbers of exosomes are increased in the maternal circulation of obese pregnant women that is mostly related to the increased lipid levels, inflammatory reactions, hyperglycemia and oxidative stress, as indicated by increase in the levels of interleukins (IL-6 and IL-8) and tumor necrosis factor (TNF-α) (Salomon et al., 2013; Rice et al., 2015; Elfeky et al., 2017; Delhaes et al., 2018). Notably, the placental EVs miRNA signature (particularly mir-517A and mir-518B) is markedly correlated with the conditions of the placenta (Luo et al., 2009). These miRNAs showed dramatic decrease after the delivery that clearly indicated about the placental functionality during pregnancy (Luo et al., 2009). Interestingly, amniotic fluid EVs reflect the oxidative stress status of the embryonic cells. Additionally, the high-mobility group box 1 (HMGB1) and cell-free fetal telomere fragments (cffTF) contents in the amniotic fluid EVs were all increased in the damaged and senescence-induced oxidative stressed amniotic epithelial cells (Sheller-Miller et al., 2017). Amnion epithelial cells EVs characteristics, heat shock protein (HSP) 70 contents, and the activated form of pro-senescence and term parturition associated marker p38 mitogen activated protein kinase (MAPK) (P-p38 MAPK) were all elevated after exposure to oxidative stress (Sheller et al., 2016). Furthermore, maternal exposure to alcohol alters the amniotic fluid EVs miRNA contents (upregulated let-7g, 25-3p, 199a-3p and 214-3p and downregulated 206-3p and 22-3p) and showed significant molecular effects on stem cell regulation and differentiation (Tavanasefat et al., 2020).

2) Genetic diseases

In the last few years, studies have explained that large sized EVs contain packaged DNA molecules and could be released from fetal origins (Hahn et al., 2014; Repisk? et al., 2018; Kone?n? et al., 2019). Therefore, plasma cell-free or exosomal DNA can be a marker for the genetic diseases and follow up of the pregnancy complications till term and delivery (Kone?n? et al., 2019). Interestingly, the DNA-associated micro-particles (MPs) in maternal plasma express fetal-derived human leukocyte antigen-G (HLA-G) or placental alkaline phosphatase (PLAP) are increased in the second trimester of pregnant women and further increased in pre-eclampsia patients (Orozco et al., 2009). Another form of the EVs, the apoptotic nanoparticles enriched with stable DNA strands, was significantly increased in the pregnancy complications such as pre-eclampsia (Orozco et al., 2008).

3) Early embryo and Fetal growth

EVs could play an important marker for the monitoring of embryonic growth and health status (Yang et al., 2020). The concentrations of placental EVs (positive for placental alkaline phosphatase/CD63) were significantly reduced in case of fetal growth restriction (FGR) (Miranda et al., 2018).

Furthermore, the EVs contents of miR-20b-5p, miR-942-5p, miR-324-3p, miR-223-5p, and miR-127-3p were increased in the maternal serum of small-for-gestational ages infants, while miR-661, miR-212-3p, and miR-197-3p were elevated in the maternal serum of large-for-gestational age infants (Rodosthenous et al., 2017). Moreover, there was a correlation between the levels of miRNAs (miR-483-5p, miR-10a-5p, miR-204-5p, miR-202-3p, miR-345-5p, miR-885-5p, miR-127-3p, miR-148b-3p, miR-324-3p, miR-1290, miR-597-5p, miR-139-5p, miR-215-5p, and miR-99b-5p) and the birth weight-for-gestational age z-score as non-invasive biomarkers of monitoring the fetal growth during pregnancy (Rodosthenous et al., 2017).

Interestingly, deep sequencing studies revealed that the EVs contents of miR-25, miR-16b, and miR-3596 were significantly increased in case of early embryonic-mortality on day-17 and day-24 of pregnancy in cattle (Pohler et al., 2017).

The numbers of placenta derived-EVs in the maternal plasma were dramatically increased with the gestational age (i.e., third trimester vs. second trimester vs. first trimester) and these EVs were able to improve the endothelial cell migration as a step forward to healthy circulation during placentation (Salomon et al., 2014).

Proteomic contents of amniotic fluid EVs of placental alkaline phosphatase/CD63 markers are increased in the normal term labor (TL), spontaneous preterm birth (PTB), and preterm premature rupture of membranes (pPROM) when compared with term not in labor (TNIL). The amniotic fluid EVs were also increased in PTB compared with pPROM (Dixon et al., 2018). Amniotic fluid EVs concentrations were also positively correlated with the number of pregnancies and the HSP contents were increased by the mid-trimester and may contribute to immune regulation within the amniotic cavity (Asea et al., 2008).

4) Gestational diabetes

One of the problems associated with pregnant women in the last trimester is the insulin resistance and gestational diabetes mellitus (GDM) and its complications such as foetoplacental endothelial dysfunction (S?ez et al., 2018a). Using the EVs is a promising tool for GDM diagnosis, follow up, and appropriate interference with the affected pregnant women. The concentration of circulating EVs is proportionally correlated with the gestational age and physical condition of the pregnant women and the concentration was increased more significantly in case of GDM (Salomon et al., 2016; Liu et al., 2018). Sequencing data of EVs from GDM affected women showed variable expression of certain miRNAs, such as hsa-miR-125a-3p, hsa334 miR-99b-5p, hsa-miR-197-3p, hsa-miR-22-3p and hsa-miR-224-5p that are linked to PI3/AKT signaling and glucose metabolism/insulin resistance (Nair et al., 2018). Interestingly, EVs were isolated from the human umbilical vein endothelium of normal and GDM-affected women and supplemented to the endothelium. EVs from GDM showed delayed wound healing for the endothelium when compared with the normal EVs. Moreover, EVs of GDM increased L-arginine transport, hCAT-1 and eNOS expression and activity, reactive oxygen species, and p44/42mapk activation in the endothelium (S?ez et al., 2018b).

5) Preeclampsia and placenta dysfunction (preterm labor)

Preeclampsia is a pregnancy disorder clinically recognized by increased systolic blood pressure and symptoms of liver and kidney damages. Preeclampsia often appears on the 20th weeks of pregnant women whose blood pressure had been normal (Roberts and Cooper, 2001). Several research groups unraveled the essential diagnostic roles of the EVs as well as the mediation of preeclampsia pathogenesis and other placental disorders (van der Post et al., 2011; Mitchell et al., 2015; Tsochandaridis et al., 2015; Gilani et al., 2016; Cuffe et al., 2017; Ermini et al., 2017; Pillay et al., 2017; Salomon and Rice, 2017; Tannetta et al., 2017a; Tannetta et al., 2017b; Jin and Menon, 2018; Morgan, 2018; Salomon et al., 2018).

It has been found that the relative concentration of placental-derived EVs increased in early onset preeclampsia but decreased in late onset preeclampsia compared to the normal pregnancy. The ratio of PLAP+ EVs/total number of EVs was reduced in early onset preeclampsia and late onset preeclampsia (Pillay et al., 2016). It has been reported that the placental protein 13 (PP13) was reduced in placental derived syncytiotrophoblast extracellular vesicles in preeclampsia suggesting its pathophysiological role in the maternal circulation (Sammar et al., 2018).

Syncytiotrophoblast EVs were increased in numbers and showed altered molecular loads and modulated the exaggerated inflammatory state during preeclampsia (G?hner et al., 2017). Furthermore, higher levels of neprilysin have been identified in preeclampsia EVs that possesses a pathological role in preeclampsia-associated hypertension, heart failure, and amyloid deposition (Gill et al., 2019).

Interestingly, miR-141 expression was increased in the placentae from preeclampsia patients and its inhibition in trophoblasts decreased cellular viability and invasion capabilities (Ospina-Prieto et al., 2016). Additionally, the level of circulating exosomal hsa-miR-210 was increased in preeclampsia placentas (Bir? et al., 2019). It is known that hsa-miR-210 significantly impacts the cellular viability, metabolic activity, and invasion capability of trophoblasts (Muralimanoharan et al., 2012; Luo et al., 2016; Hayder et al., 2021). Moreover, syncytin-2 was found to be reduced in serum-derived EVs from women with preeclampsia when compared to the normal pregnancy (Vargas et al., 2014).

The concentration of EVs was increased in extravillous trophoblast cultured under 1% compared to 8% O2. Moreover, hundreds of miRNAs were identified in extravillous trophoblast EVs and were associated with cellular migration and cytokine generation. Furthermore, EVs from extravillous trophoblast cultured at 8% O2 increased the endothelial cells migration when compared with those cultured at 1% O2 (Truong et al., 2017).

Pre-term birth is another problem associated with placental dysfunctions and can lead to lifelong complications of the pre-term born babies. Several miRNAs have been identified in the EVs of the preterm births that could be a useful biomarker for predicting the pre-term birth. Results revealed that hsa-miR-100-5p, hsa-miR-141-3p, hsa-miR-194-5p, hsa-miR-515-5p, hsa-miR-517a-3p, hsa-miR518e-5p, hsa-miR-525-5p, hsa-miR-377-3p, and hsa-miR-483-5p are good candidates for predicting pre-term birth when analyzed in the EVs isolated from the maternal plasma (Fallen et al., 2018).

Therapeutic roles of synthetic and semi-synthetic exosomes for female infertility and pregnancy

Based on the previously mentioned roles of EVs for pathogenesis and diagnosis of pregnancy disorders, the necessity for therapeutic interventions is needed. The EVs as a drug delivery option showed several advantages. First, EVs is extracted from the patient’s own cells, and hence they are less immunogenic. Second, EVs contain lipid bilayers where they increase the cellular internalization of loaded drugs. Third, the minute size of EVs avoids the phagocytosis by immune cells. In addition, EVs showed specificity for fusion with the target cells and therefore would reduce off-target effects (Zhang et al., 2019b). Nanotechnology and nanomedicine have introduced encouraging results for the development of novel targeted delivery of drugs during the pregnancy (Zhang et al., 2019a; Hashem and Gonzalez-Bulnes, 2020; Pereira et al., 2020). Surface-functionalized plCSA binding peptide (plCSA-BP)-decorated nanoparticles could be successfully designed to target placental chondroitin sulfate A that uniquely expressed in the placenta (Zhang et al., 2019a). Similar surface-functionalized nanoparticles, liposomes, immunoliposomes, or the lipid-polymer nanoparticles and their target drug delivery for uterus and placenta to treat pre-term birth, ectopic pregnancy, and fetal growth restriction are reviewed in (Zhang et al., 2019a).

Peptide-bound liposomes are mimicking the functions of EVs and also have been used for the targeted drug delivery for pregnancy complications (Pepe and Albrecht, 2021). For instance, intravenous injection of liposomes containing the peptide CRGDKGPDC bound to insulin-like growth factor (IGF-2) enhanced placental weight in wild type animals (King et al., 2016). Similarly, miRNA can be loaded in the liposomes and used for therapeutics during pregnancy. Liposomes were decorated with the peptide CCGKRK and bound with miR-145 or miR-675 inhibitor peptide nucleic acid conjugate to suppress miR-145 or miR-675, respectively. These liposomes were injected in the pregnant mice and increased the fetal and placental weights and enhanced the human cytotrophoblast proliferation in vitro (Beards et al., 2017).

Overall, re-engineering placenta-specific EVs is a very promising approach for the development of bio-inspired and targeted drug delivery systems to treat pregnancy complications (Du et al., 2017; Arrighetti et al., 2019).

CONCLUDING REMARKS AND FUTURE PERSPECTIVES

There is a trending and encouraging data that support the potential diagnostic and therapeutic roles of EVs during the early stages of embryonic development, fetal development, and maternal health. Investigating the molecular cargo of the EVs provides a non-invasive tool for diagnostics of critical illness of the fetus and mother, and guides for natural and synthetic targeted EVs-like therapeutics.

Acknowledgements

We thank the National Research Foundation of Korea and the Brain Pool program for supporting our project.

Author Contributions

Conceptualization, I.M.S, and J.C.; writing?original draft preparation, I.M.S, B.M.T., S.B., X.F., K.Y., S.L., and J.C.; writing?review and editing, I.M.S, B.M.T., S.B., X.F., K.Y., S.L., and J.C.; supervision, J.C.; project administration, J.C.; funding acquisition, J.C.

Funding

This work was supported by the Ministry of Science and ICT through the National Research Foundation of Korea (NRF) (grant No. 2021R1A2C2009294) and the Brain Pool program (grant No.: 2021H1D3A2A02040098).

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent to Publish

Not applicable.

Availability of Data and Materials

Not applicable.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.The diagnostic roles of extracellular vesicles (EVs) derived from different stages of pregnancy. EVs express tetraspanins such as CD9, CD63, and CD81. EVs interplay during embryo implantation, secreted in all biological fluids (amniotic fluid and blood) of the fetus and maternal circulation, and can be a marker for placental functions. Isolating and charactering EVs would be a helpful tool to diagnose and monitor gestational pathophysiology such as maternal health, embryo growth, gestational diabetes, and preeclampsia.
Journal of Animal Reproduction and Biotechnology 2022; 37: 2-12https://doi.org/10.12750/JARB.37.1.2

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