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Wu, H.;  Chen, L.;  Hsu, L.;  Lai, C.; Hsu, L. Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication. Encyclopedia. Available online: (accessed on 30 November 2023).
Wu H,  Chen L,  Hsu L,  Lai C, Hsu L. Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication. Encyclopedia. Available at: Accessed November 30, 2023.
Wu, Hsien-Ming, Liang-Hsuan Chen, Le-Tien Hsu, Chyong-Huey Lai, Le-Tien Hsu. "Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication" Encyclopedia, (accessed November 30, 2023).
Wu, H.,  Chen, L.,  Hsu, L.,  Lai, C., & Hsu, L.(2022, November 09). Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication. In Encyclopedia.
Wu, Hsien-Ming, et al. "Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication." Encyclopedia. Web. 09 November, 2022.
Embryonic-Derived Extracellular Vesicles in Embryo–Endometrial Communication
Embryo–endometrial communication plays a critical role in embryo implantation and the establishment of a successful pregnancy. Successful pregnancy outcomes involve maternal immune modulation during embryo implantation. The endometrium is usually primed and immunomodulated by steroid hormones and embryo signals for subsequent embryo implantation and the maintenance of pregnancy. Evidence shows that endometrial EVs and trophectoderm-originated EV cargo, including microRNAs, proteins, and lipids in the physiological microenvironment, regulate maternal immunomodulation for embryo implantation and subsequent pregnancy. On the other hand, trophoblast-derived EVs also control the cross-communication between the trophoblasts and immune cells. The exploration of EV functions and mechanisms in the processes of embryo implantation and pregnancy will shed light on a practical tool for the diagnostic or therapeutic approaches to reproductive medicine and infertility.
decidual stromal cell endometrium extracellular vesicle

1. Introduction

The embryo–endometrial communication has a critical role in the successful embryo implantation and pregnancy [1]. Maternal immune modulation during embryo implantation and subsequent pregnancy provides a tolerant microenvironment to keep the fetus from rejection [2]. Since the first human IVF baby was born in 1978, pregnancy and live birth rates following assisted reproductive technologies have improved significantly. Even so, there is still a gap in achieving higher pregnancy and live birth rates, attributed to unresolved problems in embryo quality, endometrium receptivity, and embryo–endometrium interaction [3][4]. Usually, a steroid hormone primes the endometrium for the receptive phase; after that, it is further immunomodulated by embryo signals for subsequent embryo implantation and maintenance of pregnancy [5]. Therefore, successful embryo implantation and the ensuing pregnancy depend on the coordinated interaction between the endometrium and embryos. The classical embryo–endometrial interactions through dynamic intracellular and secreted protein alterations in the stage of embryo implantation are performed to promote the successful maintenance of pregnancy [6]. The role of extracellular vesicles (EVs) and microRNAs in the decidualization for the embryo–maternal interactions of decidual endometrial stromal cells has been clarified in the implantation of the embryos [7]. EVs are cell-originated membranous vesicles that deliver bioactive molecules from cells to cells [8].

2. Decidualization of the Human Endometrium

The endometrium experiences regeneration, differentiation, and shedding during the human menstrual cycle. Usually, the endometrium in the menstrual period undergoes three main stages: the proliferative phase, the secretory phase, and the menstrual phase. Two ovarian steroid hormones, estrogen (E2) and progesterone (P4), regulate the endometrial cycle. E2 and P4 functionally and morphologically control the endometrial epithelial, stromal, and immune cells [9]. After the E2-primed proliferative phase, the proliferated endometrial epithelial and stromal cells differentiate into decidual cells in response to increasing P4 in the secretory phase [10]. The corpus luteum-synthesized and released P4 is required for promoting embryo implantation and the maintenance of placentation [11].

2.1. Morphological Differentiation in the Human Endometrium

During embryo implantation and pregnancy, the endometrium experiences decidualization in which the endometrial epithelium, stroma, and vascular structures are transformed into decidua [12][13]. The decidualization results from the elevated levels of E2 and P4 and results in a progressive change in tissue remodeling, cellular functions, and gene expression until the completion of placentation during pregnancy. During the process of decidualization, vascular endothelium, immune cells, glandular epithelium, and endometrial stromal cells react to the integration of multiple factors and mediators. After ovulation, the human endometrial stromal cells transform from fibroblast-like cells to epithelium-like cells with large pale nuclei, cytoplasmic expansion, and globular shapes in the secretory phase [14]. This transforming process features intricate cytoskeletal rearrangements [15]. The complex cytoskeletal rearrangements involve the activation of a myosin light chain and condensed F-actin, promoting intracellular remodeling [16]. P4-transformed epithelium-like decidual stromal cells produce decidual proteins, such as prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP-1), and leukemia inhibitory factor (LIF) [17][18][19].

2.2. Functional Differentiation in Human Endometrium

Progesterone receptor (PR) expression plays a role in the signaling pathways supporting endometrial homeostasis for embryo implantation and pregnancy. PRs are nuclear receptors including two isoforms (PR-A and PR-B) with disparate functions [20]. PRs appear throughout pregnancy [21], indicating that the expression level of the PRs in the human decidua is the consequence of an integrated E2 and P4 regulation and autoregulation of its promoter region [22][23]. Ligand-binding PRs are enrolled to P4 response elements in the promoters of target genes and regulates their transcription [24]. PR pathways with accumulations of cAMP promote the expression of decidual transcriptional regulators, epigenetic modifications, coordination of signal transductions, and post-transcriptional moderation [13]. The physiological role of the dynamic expression of PRs in the endometrium as decidualization initiation and ongoing pregnancy could denote the intrinsic mechanism for a functionally dynamic progesterone change [22]. The initiation of the decidualization induces decidual stromal cells to produce angiogenic factors, growth factors, cytokines, and chemokines related to blastocyst implantation.
Consequently, decidual stromal cells release numerous proteins, such as IGFBP-1 and PRL. IGFBP-1 and PRL induce trophoblast invasion and proliferation through the integrins and PRL receptors [25][26]. Through PRL, IGFBP-1, fibronectin, and PR response element signaling, the integrated regulation between the steroid hormones and their receptors delivers important messages that govern decidual transformation and endometrial immune homeostasis for embryo implantation and pregnancy [27][28]. LIF and interleukin (IL)-11 upregulate the expression of adhesion molecules and the adherence of endometrial epithelial cells to collagen IV and fibronectin [29]. LIF activates the adhesion molecules in trophoblasts and increases the attachment of trophoblasts to laminin and fibronectin (elements of the extracellular matrix); meanwhile, IL-11 enhances the adherence of endometrial epithelial cells to trophoblasts [29][30][31]. These LIF- and IL-11-induced effects promote the adhesion and invasion of the blastocyst and maintain the subsequent placentation [30][32].

3. The Content of Extracellular Vesicles

Due to the cellular origin and pathophysiological condition, EVs deliver many different bioactive molecules, including DNA, RNA (mRNA and microRNA), protein, and lipids [33]. EVs from the endometrium carry different microRNAs and proteins, periodically regulated by the ovarian steroid hormones [34].

3.1. microRNA

Recent studies indicate that microRNAs establish immune tolerance at embryo implantation and pregnancy and may contribute to the regulatory effects of T regulatory and dendritic cells. MicroRNAs were also demonstrated to modulate inflammatory and hypoxic regulation in placentation [35]. During pregnancy, microRNAs contribute to endometrial receptivity, embryo implantation, placentation, following pregnancy, and labor course [36]. The microRNA-494, microRNA-923, and microRNA-30 families are expressed differentially in regulating endometrial receptivity through the leukemia inhibitory factor (LIF) [37]. Many studies show that particular microRNAs involve the modulation of the immune system during embryo implantation and pregnancy [38][39][40]. The importance of microRNAs in the regulation of immune responses through EVs during embryo implantation and pregnancy still needs to be investigated. In humans, a particular cargo of microRNAs in endometrial EVs has been demonstrated using the human endometrial cell line [41], while a total of 13 specific microRNAs were chosen and packaged in EVs. Bioinformatics analysis for microRNAs in the cargo of the EVs showed that EV-associated microRNAs regulate cell proliferation, inflammation, remodeling, and angiogenesis for embryo implantation. Some mammal studies showed that many microRNAs were recognized in the EVs from the uterine fluid of cyclic and pregnant mammals [42][43][44], and the EVs also contained some noncoding small nuclear RNA involved in the chemical modifications of other RNAs, indicating the effects of cellular function that may be regulated following the boosting of the EVs [41]. One microRNA can regulate many genes through modulating the transcription or translation. EVs usually carry many microRNAs; therefore, it is exciting to explore the physiological effects of the molecular cargo packaged within EVs for transport into the uterine microenvironment, which plays an important role in embryo implantation and pregnancy. Functional interactions between the uterus and embryo exist during embryo implantation and placenta development. EVs with microRNAs between human decidual stromal cells have been considered significant for embryo implantation and the programming of human pregnancy [7]. This newly demonstrates that the miR-138-5p- and GPR124-adjusted NLRP3 inflammasome were identified in the EVs originated from human decidual stromal cells, suggesting that the miR-138-5p, GPR124, and NLRP3 inflammasome play a potential modulatory role in the decidual programming and placenta development of human pregnancy. These results reveal a new concept regarding the role of EVs, miR-138-5p, GPR124, and NLRP3 inflammasome in normal early pregnancy and spontaneous miscarriage. MicroRNA-138-5p acts as the transcriptional regulator of the G protein-coupled receptor 124 (GPR124). Evidence suggests EV-associated microRNA-138-5p regulates embryo implantation and early pregnancy by adjusting GPR124 and downstream signalings in human decidual stromal cells [7].

3.2. Protein

In humans, proteomic analyses of endometrial EVs were demonstrated by mimicking the hormonal profile in the menstrual cycle through estrogen and progesterone treatment [45]. The proteomic analyses of endometrial EVs reveal 663 common proteins recognized in endometrial EVs, which contribute to EV biogenesis, trafficking, sorting, uptake, and recognition. In mammals, proteomic analyses of uterine EVs showed that 195 total proteins were identified [43], including macrophage migration inhibitory factor, peripheral plasma membrane protein CASK, apolipoprotein E, myosin light chain kinase, β actin, ATP citrate synthase, and glycogen phosphorylase. The differences between the EV-packaged proteins and EV function may result from the sensitivity of the proteomic profiling analysis, EV extraction, and enrichment methods. The effects of human endometrial cell-derived EVs on embryo implantation and pregnancy are likely modulated by the protein cargo of EVs, and packaged proteins can regulate embryo apposition, adhesion, and implantation through promoting extracellular matrix remodeling. EVs from steroid hormone-primed ECC-1 endometrial cells contain peptidases, collagens, integrins, galectins, and laminins. Meanwhile, trophectoderm markers of early implantation (cathepsin CTSC, actin ACTA2, and phosphoglucomutase 1[PGM1]) and implantation regulators (AHNAK, S100A10, and PLAT) are also identified through proteomic analysis [45][46]. Furthermore, in the human trophectodermal cell line, HTR8/SVneo cell-associated EVs were demonstrated to enhance the expression of N-cadherin in the primary decidual stromal cell model [47]. In summary, these studies demonstrate the functional role of EVs and their cargo as a mediator of embryo implantation and pregnancy through contribution to maternal–embryo communication.

3.3. Lipids

The cargo of EVs also contains lipids, which include lipids, lipid metabolites, and specific enzymes for lipid metabolism that can adjust the behavior and function of targeted cells [48]. There is evidence that RNA and protein are the main cargo of uterine EVs in embryo implantation and pregnancy. However, new evidence in mammals demonstrated that the lipid profiling of uterine EVs extracted from pregnant and cyclic mammals expressed eight classes of lipids, which vary significantly between EVs from pregnant and cyclic mammals, suggesting that these classes of lipids are involved in different pregnancy phases [49].
A few studies on the role of sphingolipids have demonstrated that sphingolipids isolated from pregnancy induce prostaglandin E2 secretion in decidual stromal cells [50], and sphingolipids are involved in decidual stromal cell apoptosis through inducing p38 MAPK phosphorylation and caspase 9 activations [51]. More studies showed that sphingolipids’ pathways and their receptors are individually modulated during the decidualization of human endometrial stromal cells [52], and the estrogen- and progesterone-primed decidualization of human endometrial stromal cells reveal different expressions of sphingolipids and their receptors during pregnancy progression in response to numerous pregnancy hormones. During embryo implantation and pregnancy, angiogenesis is a critical step to enhance decidualization and placentation. Some studies showed that sphingolipids regulate the endothelial cell invasion in human umbilical vein endothelial cells and ovine uterine artery endothelial cells [53], suggesting that sphingolipids induce angiogenesis for decidualization and placentation by functioning directly on the decidual stromal and endothelial cells. However, this still needs more studies to confirm.

4. Physiological and Immunological Functions of Extracellular Vesicles

In mammal studies, embryos and endometrium could release EVs into their surrounding environment, and these embryo- and endometrium-associated EVs possibly work together to affect embryo development, embryo–endometrial interaction, embryo implantation, and following pregnancy in a paracrine and/or autocrine manner.

4.1. The Immune Modulatory Effects of Extracellular Vesicles

In mammals, during embryo implantation and early pregnancy, the embryo locates and attaches to the endometrium, followed by the invasion of cytotrophoblasts to the decidua with communication with the maternal immune system. The maternal immune system usually needs to reply to embryo implantation timely and appropriately because of the direct communication between cytotrophoblasts and decidual immune cells [54][55][56]. The first study on maternal immune tolerance and modification to the semiallogenic fetus during pregnancy was reported in 1953 [57]. At the embryo–maternal junction, the maternal immune system is composed of many immune cells, which include monocytes/macrophages, natural killer cells, T lymphocytes, B cells, and dendritic cells [58]. A study identifies the effects of EVs in immune modulation during the gestational period through a proteomic analysis of protein cargo of EVs, which were isolated from the human placenta [59]. These proteins play an important role in the response to maternal immune tolerance and modulation during early pregnancy. Some studies reported the immune-suppressive effect of placenta-isolated EVs, which contain TNF-related apoptosis-inducing ligands (TRAIL) and Fas ligands (FasL). These proteins provide the local immune tolerance at the fetal–maternal junction by inducing the apoptosis of T cells [60]. HLA-G is released from the EVs, which subsequently declines as the pregnancy progresses in human pregnancies [61]. Some studies revealed that placenta-derived EVs are associated with the Treg cell differentiation and regulation process, thus involving immune tolerance [62]. It has been demonstrated that the stable release of embryo and endometrial EVs offers a protective environment for maternal–fetal communication during embryo implantation and pregnancy. It is well known that immunological tolerance to the fetal allograft must provide the development for conceptus and the subsequent maintenance of pregnancy. During the embryo attachment period, EVs seem to transport molecules potentially able to modulate the local endometrial immune system [63][64][65][66]. This stimulated or inhibited modulation appears to depend on the cargo of EVs, such as microRNAs or proteins.
There are also data supporting the notion that the trophoblasts secrete many molecules that govern the polarization of the decidual macrophage M1/M2 phenotype to modulate the maternal immune tolerance to the fetus [67][68]. EVs seem to control the crosscommunication between the trophoblasts and the immune cells. Through uptaking trophoblast-derived EVs, the monocytes seem to increase the migration and production of cytokines [69]. The progesterone-induced blocking factor (PIBF) has been considered to control NK cell activity. PIBF is identified in embryo-derived EVs, which adhere to the surface of CD4+ and CD8+ peripheral T cells and induce IL-10 synthesis [70]. This function of embryonic EVs can be inhibited by preincubation of EVs with an antiPIBF antibody, suggesting the communication between the embryo and the maternal immune system through EVs during early implantation and pregnancy [70]. Therefore, these observations imply that embryo- and endometrial-derived EVs can recruit and regulate monocytes in a cell contact-independent manner.

4.2. Communication between the Embryo and the Maternal Immune System through Extracellular Vesicles

In mammals, the preimplantation embryos stay in the uterine cavity for a while, and EVs may play a critical role in embryo–endometrial communication for implantation. The human ECC1 cell model demonstrates that endometrial EVs modulate the trophectodermal function, such as adhesive ability [45]. Meanwhile, through proteomic analysis of these endometrial EVs, many important proteins were identified, including fibronectin, total FAK, and phosphorylated FAK proteins, suggesting that these proteins likely contribute to promoting the adhesive capacity of the trophoblasts following EV uptake [45]. Furthermore, the FAK pathway has been demonstrated to play a crucial role in EV interaction within the blastocyst intercellular communication between the trophectodermal and the inner-cell-mass cells [71]. In mammal studies, endometrial EVs function as the embryo–endometrial interaction and enhance endometrial receptivity during embryo implantation and pregnancy [46][47][72][73][74]. Pretreatment with estradiol and progesterone in immortalized endometrial cell lines can alter the molecular features of EV-modulated endometrial receptivity [46][74][75]. During embryo implantation, an increased expression of CD63 and higher numbers of EVs in human endometrium were demonstrated [42]. Additionally, the functional effects of EVs from human primary decidual stromal cells on the trophectoderm that are consistent with the impact on embryo implantation and pregnancy have been demonstrated [47]. Evidence by using immortalized trophectodermal cell lines indicates that the cargo of EVs could potentially serve as regulators of endometrial receptivity for embryo implantation after EV treatment and may provide the concept in the differential diagnosis of female infertility [76]. Consequently, this recent evidence implies the potential role of EVs as modulators of embryo implantation through the contribution to embryo–endometrium interaction, indicating that the analysis of EV cargo could offer a new concept of endometrial receptivity assay in the infertility and reproductive field [77].


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