scholarly journals Recent Insights into Human Endometrial Peptidases in Blastocyst Implantation via Shedding of Microvesicles

2021 ◽  
Vol 22 (24) ◽  
pp. 13479
Author(s):  
Masato Yoshihara ◽  
Shigehiko Mizutani ◽  
Yukio Kato ◽  
Kunio Matsumoto ◽  
Eita Mizutani ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Plasma Membranes ◽  
Uterine Cavity ◽  
Active Role ◽  
Limited Information ◽  
Endometrial Cells ◽  
Trophectoderm Cells ◽  
Blastocyst Implantation ◽  
Cluster Of Differentiation ◽  
Endometrial Epithelial Cells

Blastocyst implantation involves multiple interactions with numerous molecules expressed in endometrial epithelial cells (EECs) during the implantation window; however, there is limited information regarding the molecular mechanism underlying the crosstalk. In blastocysts, fibronectin plays a major role in the adhesion of various types of cells by binding to extracellular matrix proteins via the Arg-Gly-Asp (RGD) motif. In EECs, RGD-recognizing integrins are important bridging receptors for fibronectin, whereas the non-RGD binding of fibronectin includes interactions with dipeptidyl peptidase IV (DPPIV)/cluster of differentiation (CD) 26. Fibronectin may also bind to aminopeptidase N (APN)/CD13, and in the endometrium, these peptidases are present in plasma membranes and lysosomal membranes. Blastocyst implantation is accompanied by lysosome exocytosis, which transports various peptidases and nutrients into the endometrial cavity to facilitate blastocyst implantation. Both DPPIV and APN are released into the uterine cavity via shedding of microvesicles (MVs) from EECs. Recently, extracellular vesicles derived from endometrial cells have been proposed to act on trophectoderm cells to promote implantation. MVs are also secreted from embryonal stem cells and may play an active role in implantation. Thus, crosstalk between the blastocyst and endometrium via extracellular vesicles is a new insight into the fundamental molecular basis of blastocyst implantation.

Ultrastructure of human blastocyst-endometrial interactions in vitro

Reproduction ◽  
2000 ◽  
pp. 337-350 ◽  
Author(s):  
U Bentin-Ley ◽  
T Horn ◽  
A Sjogren ◽  
S Sorensen ◽  
J Falck Larsen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Plasma Membranes ◽  
Lateral Displacement ◽  
Syncytium Formation ◽  
Surface Epithelium ◽  
Stromal Compartment ◽  
Endometrial Cells ◽  
Trophoblastic Cells ◽  
Endometrial Epithelial Cells

The interactions of seven human blastocysts with cultured endometrial cells were investigated by light microscopy and transmission electron microscopy. Trophoblastic-endometrial contact was observed at the lateral border of endometrial epithelial cells where trophoblast and endometrial epithelial cells shared apical junctional complexes and desmosomes. The first sign of penetration was invasion of a trophoblastic cytoplasmic protrusion between endometrial epithelial cells. In broad contact areas, lateral displacement of endometrial epithelial cells and formation of a peripheral pseudostratified epithelium were observed. When trophoblastic cells were interposed fully among endometrial epithelial cells, they formed a penetration cone and appeared to dislodge endometrial epithelial cells from the stromal compartment. A single penetration cone only was found in each specimen. Endometrial or trophoblastic degeneration was not observed. Formation of multinucleate (>/= three nuclei per cell) trophoblast cells was not observed, but many cells displayed areas with abrupt disappearance of well-defined plasma membranes, which is indicative of syncytium formation. In this study, adhesion and penetration occurred at the same time. The human blastocysts penetrated the endometrial surface epithelium by intrusive penetration. Epithelial penetration was achieved primarily by cellular syncytiotrophoblast-like cells and the first indications of syncytium formation were observed simultaneously with penetration of the epithelium.

scholarly journals Specific trophoblast transcripts transferred by extracellular vesicles affect gene expression in endometrial epithelial cells and may have a role in embryo-maternal crosstalk

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Masoumeh Es-Haghi ◽  
Kasun Godakumara ◽  
Annika Häling ◽  
Freddy Lättekivi ◽  
Arina Lavrits ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Culture System ◽  
Culture Media ◽  
Functional Importance ◽  
Down Regulation ◽  
Endometrial Cells ◽  
Successful Establishment ◽  
Affect Gene Expression ◽  
Endometrial Epithelial Cells

Abstract Background Successful establishment of pregnancy hinges on appropriate communication between the embryo and the uterus prior to implantation, but the nature of this communication remains poorly understood. Here, we tested the hypothesis that the endometrium is receptive to embryo-derived signals in the form of RNA. Methods We have utilized a non-contact co culture system to simulate the conditions of pre implantation environment of the uterus. We bioorthogonally tagged embryonic RNA and tracked the transferred transcripts to endometrium. Transferred transcripts were separated from endometrial transcripts and sequenced. Changes in endometrial transcripts were quantified using quantitative PCR. Results We show that three specific transcripts are transferred to endometrial cells. We subsequently demonstrate a role of extracellular vesicles (EVs) in this process, as EVs obtained from cultured trophoblast spheroids incubated with endometrial cells induced down-regulation of all the three identified transcripts in endometrial cells. Finally, we show that EVs/nanoparticles captured from conditioned culture media of viable embryos as opposed to degenerating embryos induce ZNF81 down-regulation in endometrial cells, hinting at the functional importance of this intercellular communication. Conclusion Ultimately, our findings demonstrate the existence of an RNA-based communication which may be of critical importance for the establishment of pregnancy.

scholarly journals Small RNA-seq analysis of extracellular vesicles from porcine uterine flushing fluids during peri-implantation

2019 ◽  
Author(s):  
Renwu Hua ◽  
Yueying Wang ◽  
Weisi Lian ◽  
Wenchao Li ◽  
Yu Xi ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Small Rnas ◽  
Expression Profiles ◽  
Principal Component ◽  
Hierarchical Cluster ◽  
Dependent Manner ◽  
Trophectoderm Cells ◽  
Uterine Flushing ◽  
Vital Effects ◽  
Endometrial Epithelial Cells

Abstract Background: The extracellular vesicles (EVs) of uterine flushing fluids (UFs) mediate intrauterine communication between conceptus and uterus in pigs. The small RNAs of UFs-EVs are widely recognized as important factors that influence embryonic implantation in humans, mice, cattle and sheep. Therefore, it can be hypothesized that small RNAs of UFs-EVs are essential for implantation in pigs. Results: Cup-shaped EVs of porcine UFs were isolated and characterized, and then PKH67 stained extracellular vesicles were taken up by endometrial epithelial cells and porcine trophectoderm cells in a time-dependent manner. The expression of small RNAs in these EVs on days 10 (D10), 13 (D13) and 18 (D18) of pregnancy was comprehensively profiled through sequencing. From nine libraries, a total of 152 known microRNAs (miRNAs), 43 novel miRNAs and 6248 known Piwi-interacting RNAs (piRNAs) and 110 novel piRNAs were identified. Hierarchical cluster analysis and principal component analysis suggested that the expression profiles of small RNAs in D13 group were different from those in D10 and D18 groups. Bioinformatics analysis showed that the miRNAs differentially expressed in the comparisons between D10 and D13, D13 and D18, and D10 and D18 groups were involved in important processes and pathways related to immunization, proliferation, angiogenesis, apoptosis and development, which play important roles in embryonic implantation. Conclusions: Our results reveal that EVs from porcine UFs contain various small RNAs with potentially vital effects on implantation. This research also provides resources for studies of miRNAs and piRNAs in the cross-talk between embryo and endometrium.

scholarly journals Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

2021 ◽  
Author(s):  
Dariusz Szukiewicz ◽  
Aleksandra Stangret ◽  
Carmen Ruiz-Ruiz ◽  
Enrique G. Olivares ◽  
Olga Soriţău ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Uterine Cavity ◽  
Retrograde Transport ◽  
Surrounding Tissue ◽  
Pelvic Cavity ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Estrogen Exposure ◽  
Chronic Inflammatory Condition

AbstractEndometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis.

The scattered puzzle effect: implantation disorders in chronic endometritis

GYNECOLOGY ◽  
2020 ◽  
Vol 22 (6) ◽  
pp. 93-100
Author(s):  
Victor E. Radzinsky ◽  
Mekan R. Orazov ◽  
Liliia R. Toktar ◽  
Liudmila M. Mihaleva ◽  
Pavel A. Semenov ◽  
...  
Keyword(s):  
Uterine Cavity ◽  
Special Role ◽  
Inadequate Response ◽  
Chronic Endometritis ◽  
Vitro Fertilization ◽  
Endometrial Cells ◽  
Adverse Pregnancy ◽  
Relationship Of

Chronic endometritis (CE) is defined as a state of inflammation localized in the endometrium, accompanied by edema, dissociated maturation of epithelial cells and fibroblasts, increased stromal density and the presence of plasma cell infiltrate in it. The connection between chronic inflammation in the endometrium and infertility deserves special attention. Inadequate response of immunocompetent endometrial cells, including impaired synthesis of proinflammatory cytokines, dysreceptiveness, disorders of proliferation and differentiation processes are the main links in the formation of infertility in patients with CE. Despite the fact that the presence of a normocenosis of the uterine cavity today is not in doubt this is a physiological norm, persistent bacterial infection of the endometrium is still called the main etiopathogenetic factor of CE and, therefore, the main point of application of therapeutic agents. Nevertheless, a number of works have emphasized the special role of not bacterial, but viral etiology of endometritis, especially in the context of infertility developing against this background. It seems that the role of viral endometrial infection in adverse pregnancy outcomes and in vitro fertilization programs is underestimated. Further research is needed to clarify the relationship of viral infection as a trigger of implantation failure in infertile women with CE.

scholarly journals Lipocalin 2 induces the epithelial–mesenchymal transition in stressed endometrial epithelial cells: possible correlation with endometriosis development in a mouse model

Reproduction ◽  
2014 ◽  
Vol 147 (2) ◽  
pp. 179-187 ◽  
Author(s):  
Chi-Jr Liao ◽  
Pei-Tzu Li ◽  
Ying-Chu Lee ◽  
Sheng-Hsiang Li ◽  
Sin Tak Chu
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Lipocalin 2 ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Cellular Microenvironments ◽  
And Migration ◽  
Endometrial Epithelial Cells

Lipocalin 2 (LCN2) is an induced stressor that promotes the epithelial–mesenchymal transition (EMT). We previously demonstrated that the development of endometriosis in mice correlates with the secretion of LCN2 in the uterus. Here, we sought to clarify the relationship between LCN2 and EMT in endometrial epithelial cells and to determine whether LCN2 plays a role in endometriosis. Antibodies that functionally inhibit LCN2 slowed the growth of ectopic endometrial tissue in a mouse model of endometriosis, suggesting that LCN2 promotes the formation of endometriotic lesions. Using nutrient deprivation as a stressor, LCN2 expression was induced in cultured primary endometrial epithelial cells. As LCN2 levels increased, the cells transitioned from a round to a spindle-like morphology and dispersed. Immunochemical analyses revealed decreased levels of cytokeratin and increased levels of fibronectin in these endometrial cells, adhesive changes that correlate with induction of cell migration and invasion.Lcn2knockdown also indicated that LCN2 promotes EMT and migration of endometrial epithelial cells. Our results suggest that stressful cellular microenvironments cause uterine tissues to secrete LCN2 and that this results in EMT of endometrial epithelial cells, which may correlate with the development of ectopic endometriosis. These findings shed light on the role of LCN2 in the pathology of endometrial disorders.

scholarly journals Multiple endometrial polyps in patient undergoing long-term gestagen therapy

2005 ◽  
Vol 133 (9-10) ◽  
pp. 438-440
Author(s):  
Milena Zamurovic ◽  
Pavle Srbinovic ◽  
Jovana Petrovic
Keyword(s):  
Progesterone Receptors ◽  
Uterine Cavity ◽  
Reproductive Period ◽  
Histopathological Analysis ◽  
Endometrial Polyps ◽  
Endometrial Cells ◽  
Gynecology And Obstetrics ◽  
Irregular Bleeding ◽  
Continuous Presence ◽  
Cell Genome

Endometrial polyps represent a limited focal, circumscribed overgrowth of the endometrium. Their aetiopathogenesis has not been completely explained yet. They are often found in perimenopausal women; during the reproductive period they are less common. We present the case of a 32-year-old patient, who came for a check-up to the Gynecology and Obstetrics Clinic "Narodni Front" because of irregular bleeding. The patient was subjected to hormonal linestrenol therapy, which she had administered herself, without further consultations with her gynecologist, during the previous 10 years. Complete diagnostic examinations were performed. Contrast sonohysterography enabled the visualization of multiple polyps inside the uterine cavity, which were confirmed by histopathological analysis of material obtained via explorative curettage. Histopathological material contained over 30 endometrial polyps. A control check-up after one month, as well as subsequent quarterly check-ups, resulted in normal findings. Analysis of the described case has indicated that the loss of sensitivity of progesterone receptors in endometrial cells is possible if there is a continuous presence of progesterone agonists in circulation, as is true of linestrenol in this case. The loss of sensitivity of progesterone receptors upsets normal hormonal activity during the secretory phase of the menstrual cycle, leading to copious, irregular bleeding. These changes may, however, have even deeper effects. More recent research shows that, if the agent causing the loss of sensitivity of the receptors is present in circulation over a longer time period, changes may also appear at the DNA molecular level, i.e. in the cell genome itself. This, in turn, may lead to the beginning of the process of oncogenesis and the formation of timorous tissue.

Changes in the fine structure of the apical plasma membrane of endometrial epithelial cells during implantation in the rat

1982 ◽  
Vol 55 (1) ◽  
pp. 1-12
Author(s):  
C.R. Murphy ◽  
J.G. Swift ◽  
T.M. Mukherjee ◽  
A.W. Rogers
Keyword(s):  
Plasma Membrane ◽  
Fine Structure ◽  
Epithelial Cells ◽  
Normal Pregnancy ◽  
Ovariectomized Rats ◽  
Apical Plasma Membrane ◽  
Embryonic Cells ◽  
Blastocyst Implantation ◽  
First Contact ◽  
Endometrial Epithelial Cells

In previous work we have shown that ovarian hormones, when injected into ovariectomized rats, alter the fine structure of the plasma membrane of endometrial epithelial cells. In this paper freeze-fractures have been used to study the apical plasma membrane of endometrial epithelial cells of rats during the period of blastocyst implantation of normal pregnancy. On day 1 of pregnancy there were 2354 +/− 114 intramembranous particles (IMPs) per micrometer2 of membrane. The particles were spherical and randomly distributed. On day 5 of pregnancy IMP density rose to 2899 +/− 289 per micrometer2 and some rod-shaped particles were also visible. By day 6 of pregnancy IMP density had risen to 4014 +/− 206 per micrometer2 and there were more rod-shaped IMPs than before. In addition, on day 6 IMPs were also present as rows of particles and some gap-junction-like arrays of particles were also seen. Our findings indicate that there are fine-structural alterations in the apical plasma membrane of endometrial epithelial cells, the site of first contact between maternal and embryonic cells, during the period of early pregnancy. The findings are discussed in the light of suggested mechanisms of blastocyst attachment to the uterine epithelium at implantation.

P–388 Endometrial extracellular vesicles from recurrent implantation failure patients inhibited embryonic growth and implantation via miR–6131/PAK2 pathway

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
C Liu
Keyword(s):  
Extracellular Vesicles ◽  
Migration And Invasion ◽  
Hatching Rate ◽  
Implantation Failure ◽  
Trophoblast Cells ◽  
Recurrent Implantation Failure ◽  
Endometrial Cells ◽  
Blastocyst Rate ◽  
Fertile Women

Abstract Study question Could endometrial extracellular vesicles from recurrent implantation failure patients (RIF-EVs) attenuate the growth and implantation potentials of embryos and what are the mechanisms? Summary answer: RIF-EVs inhibited embryonic growth and decreased the trophoblast functions via miR–6131/PAK2 pathway. What is known already Recurrent implantation failure (RIF) is characterized by repeated embryo transfers without pregnancy. To date, the etiology of RIF remains poorly understood. Recent evidence indicated that extracellular vesicles (EVs) secreted by endometrial cells, played a crucial role in the implantation by regulating the development and implantation of embryos. Study design, size, duration Endometrial cells isolated from endometrial tissues of RIF patients (n = 25) and fertile women (n = 16) were cultured and modulated via hormones. Endometrial EVs from RIF patients (RIF-EVs) or fertile women (FER-EVs) were isolated from the conditioned medium. The influence of EVs on embryonic development and implantation was investigated by co-culture models of EVs and 2-cell murine embryos or HTR8/SVneo cells, respectively. High-through put sequencing was performed to identify the miRNA profile in the RIF-EVs. Participants/materials, setting, methods RIF-EVs and FER-EVs were characterized using western blotting, nanoparticle tracking analysis, and transmission electron microscopy. After co-culture with EVs, embryonic blastocyst rate and hatching rate were calculated. Besides, the proliferation, migration, and invasion of EV-treated trophoblast cells were evaluated by CCK–8, wound healing, and transwell invasion assays. miRNA expression profiles were compared between RIF-EVs and FER-EVs, and the regulatory role of significantly upregulated miR–6131 in RIF-EVs was investigated in the trophoblast cells. Main results and the role of chance RIF-EVs and FER-EVs are round bilayer vesicles, ranging mainly at 100 nm and enriched in TSG101, Alix, and CD9. Both RIF-EVs and FER-EVs entered embryonic or trophoblast cytoplasm. The blastocyst rate in the RIF-EV groups was significantly decreased compared to that in the FER-EV groups, at concentrations of 5, 10, and 20 μg/ml. The hatching rate was decreased significantly in embryos treated with 10 or 20 μg/ml RIF-EVs compared to those treated with FER-EVs at the same concentration (p < 0.05). The proliferation, migration, and invasion of trophoblasts were significantly decreased in the RIF-EV group at 20 μg/mL. A total of 11 differently expressed (fold change >2 and p < 0.05) miRNAs were found in the RIF-EVs, and two of them were validated in a larger set of EV samples using RT-PCR. The most significantly different miRNA, 6131, was increased in the RIF-EV-treated HTR8/SVneo cells. The up-regulation of miR–6131 inhibited the growth and invasion of HTR8/SVneo. Bioinformatics coupled with luciferase and western blot assays revealed that PAK2 is a direct target of miR–6131, and the overexpression of PAK2 can rescue the phenotype changes induced by miR–6131 overexpression. Limitations, reasons for caution Our study indicated miRNA in the RIF-EVs dysregulating the growth and function of embryonic cells. However, EVs contained a wide spectrum of bioactive molecules, including proteins, mRNAs, and DNA, which may play an important role in the implantation. Further studies are required to investigate the mechanisms. Wider implications of the findings: This work indicates an important role of EVs from women with RIF in embryonic implantation, potentially providing a novel insight to understand the pathophysiology of RIF. Trial registration number Not applicable

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