Adhesion Of Endometrial Cells Research Articles

N-Myc and STAT Interactor is an Endometriosis Suppressor.

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3 and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including β-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure.

Yikang decoction facilitates embryo implantation in mice with implantation dysfunction via upregulation of LIF expression

ObjectiveThe present study investigates the effects and mechanisms of Yikang decoction on embryo implantation in mice. MethodsTotally, mature female mice were randomly divided into four groups: normal, implantation failure (mifepristone treatment), Yikang decoction treatment (mifepristone and Yikang decoction treatment), and control (mifepristone and physiological saline treatment) groups. The efficacy of Yikang decoction was evaluated by the adhesion of uterine endometrial cells. The expression of leukemia inhibitory factor (LIF) and integrin αvβ3 in the endometrium were detected by real-time quantitative PCR and western blot. In addition, mouse endometrial cells were transfected with LIF specific siRNA-1, and the expression of LIF and αvβ3 were detected. ResultsThe number of embryos markedly decreased after mifepristone treatment. The adhesion of endometrial cells in the Yikang decoction treatment group significantly increased, when compared to the control group. The expression of LIF and integrin αvβ3 was significantly reduced by mifepristone, but the attenuated expression of LIF and αvβ3 was markedly reversed by treatment with Yikang decoction. In addition, after LIF siRNA-1 transfection, the expression of integrin αvβ3 significantly decreased (P < 0.01). The correlation analysis revealed a significant positive correlation between LIF and αvβ3 protein expression. ConclusionYikang decoction can regulate the expression of αvβ3 and increase cell adhesion by upregulating the expression of LIF, thereby improving embryo implantation in mice. These data suggest that Yikang decoction may have therapeutic effect in treating infertility.

The effect of acetylsalicylic acid on pain and recurrence of endometriosis after surgery: A randomized controlled trial

Background: Reactive oxygen species (ROS) might increase growth and adhesion of endometrial cells in the peritoneal cavity, and lead to endometriosis. In this study the we evaluate the effect of an antioxidant, acetylsalicylic acid (aspirin), to determine whether aspirin administration to patients with endometriosis would affect pelvic pain and disease recurrence. Material and methods: This randomized controlled trial was conducted from March 2018 to March 2020 on women, 19 to 40 years of age, who were diagnosed with endometriosis after undergoing laparoscopic surgery. Study participants were randomly assigned to one of two groups, Oral contraceptive pills (OCP) and placebo or OCP and aspirin, which were administered daily for 6 months. Pelvic pain, dysmenorrhea, mass size, and menstrual bleeding were evaluated at 3 and 6 months. Results: There were 38 patients in the aspirin group and 49 participants in the placebo group. The mean dysmenorrhea Visual analog scale (VAS) score after 3 months was 2.24 in the aspirin group and 3.61 in the placebo group. After 6 months, the dysmenorrhea VAS scores were 0.68 (aspirin group) and 2.69 (placebo group) ( p = 0.005 and p = 0.00, respectively). Dyspareunia and pelvic pain showed significant reductions ( p = 0.00). Six patients in the control group and four patients in the aspirin group experienced lesion recurrence ( p = 0.45). Conclusion: The results suggest that aspirin, as an antioxidant, could effectively reduce pain in women with endometriosis. However, additional studies that enroll larger numbers of participants and long-term follow up will enable better evaluation of recurrence.

Talin1 regulates endometrial adhesive capacity through the Ras signaling pathway

AimsBlastocyst implantation is mainly depended on the adhesion between cells and cell matrix. Endometrial adhesion plays an important role in establishing embryo implantation, but the underlying mechanisms are remains unclear. Talin1 is a local adhesion complex protein that is necessary for cell adhesion and movement. However, the role and mechanisms of Talin1 in embryo implantation are still unclear. Main methodsThe expression of Talin1 and Integrin αvβ3 was measured in the receptive endometrium from the RIF (Recurrent implantation failure) cohort and NC (normal fertile control group) cohort. A JEG-3 trophoblast and endometrial epithelial cell adhesion model and pregnant mouse model were established. The molecular mechanism of Talin1-mediated cell adhesion was explored by RNA sequencing, RT-qPCR, as well as western blotting assays. Key findingsTalin1 enhances endometrial cell adhesion by regulating the Ras signaling pathway, and ultimately facilitates embryo implantation. SignificanceThis study revealed the molecular mechanisms of regarding the pathogenesis of RIF caused by endometrial receptivity insufficiency. Further pharmacological research on the Ras signaling pathway would be valuable and might provide new therapeutic targets for RIF patients.

Talin1 Regulates Endometrial Adhesive Capicity Through the Ras Signaling Pathway

Background: Blastocyst implantation is mainly depended on the adhesion between cells and cell matrix. Endometrial adhesion plays an important role in establishing embryo implantation, but the underlying mechanisms are remains unclear. Talin1 is a local adhesion complex protein that is necessary for cell adhesion and movement. However, the role and mechanisms of Talin1 in embryo implantation are still unclear. Methods: The expression of Talin1 and Integrin αvβ3 was measured in the receptive endometrium from the RIF (Recurrent implantation failure) cohort and NC (normal fertile control group) cohort. A JEG-3 trophoblast and endometrial epithelial cell adhesion model and pregnant mouse model were established. The molecular mechanism of Talin1-mediated cell adhesion was explored by RNA sequencing, RT-qPCR, as well as western blotting assays. Findings: Talin1 enhances endometrial cell adhesion by regulating the Ras signaling pathway, and ultimately facilitates embryo implantation. Interpretation: This study revealed the molecular mechanisms of regarding the pathogenesis of RIF caused by endometrial receptivity insufficiency. Further pharmacological research on the Ras signaling pathway would be valuable and might provide new therapeutic targets for RIF patients. Funding: This study was supported by grants from the National Natural Science Foundation of China and the Natural Science Foundation of Guangxi Zhuang Autonomous Region and the Guangxi Medical University Training Program for Distinguished Young Scholars Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: All participants provided written informed consent, and the study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. All animal experimental procedures were approved by the animal ethics committee of Guangxi Medical University in accordance with animal research guidelines.

Talin1 Improves Endometrial Receptivity Through the Ras Signaling Pathway

Background: Blastocyst implantation mainly depends on the adhesion between cells and the cell matrix. Endometrial adhesion plays an important role in establishing endometrial receptivity, but its molecular mechanism remains unclear. Talin1 is a local adhesion complex protein necessary for cell adhesion and movement. However, the role and mechanism of Talin1 in embryo implantation remain unclear. Methods: The expression levels of Talin1 and Integrin αvβ3 were measured in the receptive endometrium from the URPL cohort and NC cohort. A JEG-3 trophoblast and endometrial epithelial cell adhesion model and pregnant mouse model were established. The molecular mechanism of Talin1-mediated regulation of cell adhesion was explored by adhesion experiments, RNA sequencing, RT-qPCR and western blotting assays. Findings: Talin1 enhances endometrial cell adhesion and endometrial receptivity by regulating the activity of the Ras signaling pathway, and it ultimately facilitates embryo implantation. Interpretation: This study revealed the specific molecular mechanism of the pathogenesis of UPRL caused by endometrial receptivity insufficiency in cell and animal models. We should conduct additional pharmacological research on the Ras signaling pathway and provide new therapeutic targets for URPL. Funding: This study was supported by grants from the National Natural Science Foundation of China and the Natural Science Foundation of Guangxi Zhuang Autonomous Region and the Guangxi Medical University Training Program for Distinguished Young Scholars Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: All participants provided written informed consent, and the study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University. All animal experimental procedures were approved by the animal ethics committee of Guangxi Medical University in accordance with animal research guidelines.

The effect of N-butyl benzyl phthalate, a common plasticizer, on endometriosis development

Abstract Endometriosis is an estrogen-dependent and chronic inflammatory disease, which retrograded menstrual endometrial cells enter the pelvis and abnormally grow outside the uterine cavity. Severe symptoms such as infertility and chronic pelvic pain are typically observed in 6%–10% of reproductive-aged women. Previous study demonstrates that phthalates are capable to disrupt the endocrine system, especially by mimicking estrogen functions. Among them, n-butyl benzyl phthalate (BBP), a plasticizer for vinyl foams and artificial leather, is able to work as a selective agonist through the binding of ERα, and subsequently interrupt the endocrine regulation. This study aimed to explore the effect of BBP on endometriosis. We established a surgery-induced murine model and exposed the mice at physiologically relevant dose of BBP mimicking human exposure. The result showed that chronic exposure to BBP did not promote the growth of endometrial lesions, however, the lesion survival rate in BBP-treated mice was significantly increased compared to vehicle-treated mice. Our data showed that BBP exposure promoted the infiltration of monocytes (Ly6c+CD11b+F4/80-) and plasmacytoid dendritic cells (pDCs; CD11c+/lowPDCA-1+) in the lesions. In addition, the percentages of CD44+ cells in the infiltrated monocytes and pDCs in the BBP-treated group were significantly higher than those in the control. Also, BBP exposure promoted ICAM-1 expression in CD45− endometriotic lesion cells. The results suggest that BBP exposure may enhance endometrial cell adhesion through altering innate cell subset migration. The detail mechanism of BBP effect on endometriosis development awaits further investigation.

Focal Adhesion Kinase-Mediated Sequences, Including Cell Adhesion, Inflammatory Response, and Fibrosis, as a Therapeutic Target in Endometriosis.

Endometriosis has several distinguishing features in the ectopic endometrium, including chronic inflammation and fibrosis. According to the retrograde menstruation theory, endometriotic cells are derived from eutopic endometrial cells, and adhesion of endometrial cells to the extracellular matrix can be the initial step in the development of endometriosis. Therefore, we hypothesized that cell adhesion, which mediates a sequence of events in the development of endometriosis triggering inflammatory responses and tissue fibrosis could be a possible therapeutic target for endometriosis. We found co-upregulation of focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 (MCP-1) in the endometriotic tissues compared with that in the normal endometrium. MCP-1 secretion was significantly higher in the endometriotic stromal cells than in the eutopic endometrial stromal cells. Furthermore, co-culture of U937 cells and endometriotic stromal cells upregulated secretion of transforming growth factor-β1 (TGF-β1). A FAK inhibitor significantly inhibited the secretion of MCP-1 in the endometriotic stromal cells and TGF-β1 in the co-culture with macrophages. FAK inhibitor treatment in the murine endometriosis model demonstrated a decrease in the formation of endometriotic lesions as well as the expression of MCP-1 and TGF-β1. Our results suggest that the FAK-mediated sequential development of endometriosis, including inflammatory response and tissue fibrosis, can be a new therapeutic target in endometriosis.

Inhibition of Hyaluronic Acid Synthesis Decreases Endometrial Cell Attachment, Migration, and Invasion.

To characterize the effects of 4-methylumbelliferone (4-MU) on expression of the hyaluronic acid (HA) system and on attachment, migration, and invasion of endometrial epithelial (EECs) and stroma cells (ESCs) to peritoneal mesothelial cells (PMCs), this in vitro study was performed in an Academic Center. De-identified endometrial tissue samples used were from reproductive-aged women. EECs and ESCs isolated from menstrual endometrial biopsies were treated with 4-MU or vehicle. Real-time polymerase chain reaction and western blot were used to assess expression of HA synthases (HAS), hyaluronidase, and standard CD44. Established in vitro assays were used to assess attachment, migration, and invasion with and without treatment with 4-MU. Chi square and Student's t-test were used to analyze the results as appropriate. The addition of 4-MU decreased mRNA and protein expression of HAS 2, HAS 3, and CD44 in EECs and ESCs compared to control. Treatment with 4-MU also decreased attachment, migration, and invasion of EECs and ESCs to PMCs compared to control. 4-MU decreases endometrial cell adhesion, migration, and invasion to PMCs. This effect appears to be mediated by a decrease in HAS 2, HAS 3, and CD44. 4-MU is a potential treatment for endometriosis. Future in vivo studies are needed to evaluate 4-MU as a therapeutic agent for endometriosis.

HHV-6A Infection of Endometrial Epithelial Cells Affects miRNA Expression and Trophoblast Cell Attachment

We recently reported that human herpesvirus 6 (HHV-6) infection is frequently present in endometrial tissue of women with unexplained infertility, and that virus infection induces a profound remodulation of miRNA expression in human cells of different origin. Since specific miRNA patterns have been associated with specific pregnancy outcomes, we aimed to analyze the impact of HHV-6A infection on miRNAs expression and trophoblast receptivity in human endometrial cells. To this purpose, a human endometrial cell line (HEC-1A) was infected with HHV-6A and analyzed for alterations in the expression of miRNAs and for permissiveness to the attachment of a human choriocarcinoma trophoblast cell line (JEG-3). The results showed that HHV-6A infection of endometrial cells up-modulates miR22 (26-fold), miR15 (19.5-fold), and miR196-5p (12.1 fold), that are correlated with implant failure, and down-modulates miR18 (11.4 fold), miR101-3p (4.6 fold), miR181-5p (4.9 fold), miR92 (3.3 fold), and miR1207-5p (3.9 fold), characterized by a low expression in preeclampsia. Moreover, HHV-6A-infected endometrial cells infected resulted less permissive to the attachment of trophoblast cells. In conclusion, collected data suggest that HHV-6A infection could modify miRNA expression pattern and control of trophoblast cell adhesion of endometrial cells, undermining a correct trophoblast cell attachment on endometrial cells.

Inhibitory effect of AQP1 silencing on adhesion and angiogenesis in ectopic endometrial cells of mice with endometriosis through activating the Wnt signaling pathway

ABSTRACTThe development mechanism of endometriosis remains unknown. Water channel aquaporin-1 (AQP1) enhances water flux across cell membranes, which is highly expressed and associated with cell migration, metastasis and angiogenesis in some human cancers. In this study, the role of the Wnt signaling pathway mediated by AQP1 in endometriosis was investigated, in a bid to provide new therapeutic targets for endometriosis. Microarray expression profiles were screened to acquired differentially expressed genes related to endometriosis. Mouse models with endometriosis were established and grouped. The level of endometriosis was evaluated by measurement of the volume of ectopic region. The expression of AQP1, pathway-related factors (Wnt1 and Wnt4), adhesion molecules (VCAM-1 and ICAM-1), invasive factors (MMP-2, MMP-9, TIMP-1 and TIMP-2), angiogenic factors (VEGF-A, VEGFR1 and VEGFR2) and apoptotic factors (Caspase-3, Caspase-9, Bax and BcL-2) was measured by RT-qPCR and western blot analysis. Furthermore, the role of AQP1 in adhesion, invasion, angiogenesis, and apoptosis of ectopic endometrial cells was determined by transfection of si-AQP1 plasmid. AQP1 was robustly expressed in endometriosis. AQP1 gene silencing alleviated the progression of endometriosis by activating the Wnt signaling pathway in mice with endometriosis. Specifically, silencing of AQP1 gene inhibited ectopic endometrial cell adhesion and invasion abilities, suppressed angiogenesis while promoted apoptosis. Collectively, the present study highlights the role of AQP1 in the regulation of the Wnt signaling pathway in endometriosis mouse models, suggesting that AQP1 could represent a new target aimed at improving the survival of patients with endometriosis.

Increased \u03b12-6 sialylation of endometrial cells contributes to the development of endometriosis

Endometriosis is a disease characterized by implants of endometrial tissue outside the uterine cavity and is strongly associated with infertility. Focal adhesion of endometrial tissue to the peritoneum is an indication of incipient endometriosis. In this study, we examined the effect of various cytokines that are known to be involved in the pathology of endometriosis on endometrial cell adhesion. Among the investigated cytokines, transforming growth factor-β1 (TGF-β1) increased adhesion of endometrial cells to the mesothelium through induction of α2-6 sialylation. The expression levels of β-galactoside α2-6 sialyltransferase (ST6Gal) 1 and ST6Gal2 were increased through activation of TGF-βRI/SMAD2/3 signaling in endometrial cells. In addition, we discovered that terminal sialic acid glycan epitopes of endometrial cells engage with sialic acid-binding immunoglobulin-like lectin-9 expressed on mesothelial cell surfaces. Interestingly, in an in vivo mouse endometriosis model, inhibition of endogenous sialic acid binding by a NeuAcα2-6Galβ1-4GlcNAc injection diminished TGF-β1-induced formation of endometriosis lesions. Based on these results, we suggest that increased sialylation of endometrial cells by TGF-β1 promotes the attachment of endometrium to the peritoneum, encouraging endometriosis outbreaks.

The Role of Oxidative Stress and Membrane Transport Systems during Endometriosis: A Fresh Look at a Busy Corner.

Endometriosis is a condition characterized by the presence of endometrial tissue outside the uterine cavity, leading to a chronic inflammatory reaction. It is one of the most widespread gynecological diseases with a 10–15% prevalence in the general female population, rising up to 30–45% in patients with infertility. Although it was first described in 1860, its etiology and pathogenesis are still unclear. It is now accepted that inflammation plays a central role in the development and progression of endometriosis. In particular, it is marked by an inflammatory process associated with the overproduction of an array of inflammatory mediators such as prostaglandins, metalloproteinases, cytokines, and chemokines. In addition, the growth and adhesion of endometrial cells in the peritoneal cavity due to reactive oxygen species (ROS) and free radicals lead to disease onset, its ensuing symptoms—among which pain and infertility. The aim of our review is to evaluate the role of oxidative stress and ROS in the pathogenesis of endometriosis and the efficacy of antioxidant therapy in the treatment and mitigation of its symptoms.

Transforming growth factor β1 enhances adhesion of endometrial cells to mesothelium by regulating integrin expression.

Endometriosis is the abnormal growth of endometrial cells outside the uterus, causing pelvic pain and infertility. Furthermore, adhesion of endometrial tissue fragments to pelvic mesothelium is required for the initial step of endometriosis formation outside uterus. TGF-β1 and adhesion molecules importantly function for adhesion of endometrial tissue fragments to mesothelium outside uterus. However, the function of TGF-β1 on the regulation of adhesion molecule expression for adhesion of endometrial tissue fragments to mesothelium has not been fully elucidated. Interestingly, transforming growth factor β1 (TGF-β1) expression was higher in endome-triotic epithelial cells than in normal endometrial cells. The adhesion efficiency of endometriotic epithelial cells to meso-thelial cells was also higher than that of normal endometrial cells. Moreover, TGF-β1 directly induced the adhesion of endometrial cells to mesothelial cells through the regulation of integrin of αV, α6, β1, and β4 via the activation of the TGF-β1/TGF-βRI/Smad2 signaling pathway. Conversely, the adhesion of TGF-β1-stimulated endometrial cells to mesothelial cells was clearly reduced following treatment with neutralizing antibodies against specific TGF-β1-mediated integrins αV, β1, and β4 on the endometrial cell membrane. Taken together, these results suggest that TGF-β1 may act to promote the initiation of endometriosis by enhancing integrin-mediated cell-cell adhesion.

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity.

Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle. The effects of miR-661 on gene expression in and adhesion of endometrial cells was also examined. MiR-661 overexpression consistently downregulated MDM2 but not MDM4 or p53 gene expression in the Ishikawa endometrial epithelial cell line and primary HEEC. Adhesion assays were performed on the real-time monitoring xCELLigence system and by co-culture using Ishikawa cells and HEECs with HTR8/SVneo trophoblast spheroids. Targeted siRNA-mediated knockdown of MDM2 in endometrial epithelial cells reduced Ishikawa cell adhesion (P<0.001) and also reduced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.05) and HEECs (P<0.05). MDM2 overexpression using recombinant protein treatment resulted in enhanced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.01) and HEECs (P<0.05). This study highlights a potential new mechanism by which human blastocyst-secreted miR-661 reduces endometrial epithelial cell adhesion; via downregulation of MDM2. These findings suggest that MDM2 contributes to endometrial-blastocyst adhesion, implantation and infertility in women.

The association between hormonal variation, antioxidant status and oxidative stress in Iraqi women with endometriosis

Background: In the last years, Endometriosis affects up to 10 percent of reproductive aged Iraqi women. Little is known about the etiology of endometriosis in Iraqi women.Objectives: The aim of this study is to investigate the hormonal changes, antioxidant status, Coenzyme Q10 and oxidative stress in women patients with endometriosis.Patients and methods: 30 endometriotic women mean aged (31.16±5.61 year ) who were undergoing laparoscopy to participate in this study, and (n=30) healthy women volunteers mean aged (31.96±5.42 year) as control group.Results: The results in this study revealed a highly significant increased (P&lt;0.01) in estradiol (E2), uric acid (UA) and oxidative stress (MDA). The results of the Coenzyme Q10 (CoQ10) and vitamins (A, E, β-carotene, C) showed a highly significant decreased (P&lt;0.01) in the sera levels of patients with endometriosis as compared to control. This study showed, there was a significant negative correlation between the levels of Luteinizing Hormone (LH), Follicle Stimulating Hormones (FSH), Testosterone (Test.), E2 and vitamins, whereas a significant positive correlation was observed in UA level with concomitant increase in MDA levels.Conclusions: The results of this study concluded the increase of oxidative stress and the decrease of antioxidant vitamins and CoQ10. Thus increasing the growth and adhesion of endometrial cells in the peritoneal cavity, which will lead to increase the risk factors of endometriosis.

Soluble CD44 concentration in the serum and peritoneal fluid samples of patients with different stages of endometriosis.

Endometriosis is a gynecological disease defined by the histological presence of endometrial glands and stroma outside the uterine cavity, most commonly implanted over visceral and peritoneal surface within the female pelvis. CD44 is a membrane protein expressed by human endometrial cells, and it has been shown to promote the adhesion of endometrial cells. The aim of this study was to determine the levels of soluble CD44 (sCD44) in the serum and peritoneal fluid (PF) samples of patients with different stages of endometriosis. 39 PF and serum samples from normal healthy and 130 samples from different stages of patients with endometriosis (33 cases of stage I, 38 stage II, 30 stage III and 29 stage IV) were included in this study. Total protein concentration (TPC) and the level of s-cMet in the serum were determined by Bio-Rad protein assay based on the Bradford dye procedure and enzyme-linked immunosorbent assay, respectively. No significant change in the TPC was seen in the serum of patients with endometriosis when compared to normal controls. Results obtained demonstrated that all serum and peritoneal fluid samples, presented sCD44 expression, whereas, starting from stages I to IV endometriosis, a significant increase of sCD44 expression was observed as compared to control group. The results of this study show that a high expression of sCD44 is correlated with advanced stages of endometriosis. It is also concluded that the detection of serum and/or peritoneal fluid sCD44 may be useful in classifying endometriosis.

MiR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model.

Endometriosis is defined as the growth of endometrial glandular and stromal components in ectopic locations and affects as many as 10% of all women of reproductive age. Despite its high prevalence, the pathogenesis of endometriosis remains poorly understood. MicroRNAs, small non-coding RNAs that post-transcriptionally regulate gene expression, are mis-expressed in endometriosis but a functional role in the disease pathogenesis remains uncertain. To examine the role of microRNA-451 (miR-451) in the initial development of endometriosis, we utilized a novel mouse model in which eutopic endometrial fragments used to induce endometriosis were deficient for miR-451. After induction of the disease, we evaluated the impact of this deficiency on implant development and survival. Loss of miR-451 expression resulted in a lower number of ectopic lesions established in vivo. Analysis of differential protein profiles between miR-451 deficient and wild-type endometrial fragments revealed that fibrinogen alpha polypeptide isoform 2 precursor was approximately 2-fold higher in the miR-451 null donor endometrial tissue and this elevated expression of the protein was associated with altered expression of the parent fibrinogen alpha chain mRNA and protein. As this polypeptide contains RGD amino acid “cell adhesion” motifs which could impact early establishment of lesion development, we examined and confirmed using a cyclic RGD peptide antagonist, that endometrial cell adhesion and endometriosis establishment could be respectively inhibited both in vitro and in vivo. Collectively, these results suggest that the reduced miR-451 eutopic endometrial expression does not enhance initial establishment of these fragments when displaced into the peritoneal cavity, that loss of eutopic endometrial miR-451 expression is associated with altered expression of fibrinogen alpha chain mRNA and protein, and that RGD cyclic peptide antagonists inhibit establishment of endometriosis development in an experimental mouse model suggesting that this approach may prove useful in the prevention of endometriosis establishment and survival.

Important Initiative Roles of CD44 and Tenascin in Sampson's Theory of the Pathogenesis and Development of Endometriosis

Background Among several theories explaining the pathogenesis of endometriosis, Sampson's theory seems to be the most reliable and popular. However, this theory does have some problems. First, the onset of endometriosis is not as common as retrograde menstruation. Second, the surface of the peritoneum is capable of preventing the adhesion of foreign bodies such as endometrial cells. Regarding the first problem, several studies on immunosurveillance have been reported. The second problems has not yet been clarified, Therefore we investigated the problem in the present report. Methods Levels of CD44 and tenascin in both menstrual and peripheral blood were assayed in 19 healthy volunteer women in the first experiment. In the second experiment, the effects of tenascin on the activity of MMP-9 were investigated, because the invasive ability of endometriotic cells is known to be due to MMP activity. Results CD44 and tenascin concentrations were significantly higher in menstrual blood than in peripheral blood. Since CD44 is a specific hyaluronic acid receptor, CD44 in menstrual blood was demonstrated to be a specific matchmaker of adhesion between the endometrial cells and the peritoneal surface. Tenascin in menstrual blood and endometriotic cells up-regulated MMP activity and promoted the invasive action of endometriotic cells. Conclusion The present study clarified that adhesion of endometrial cells in menstrual blood on adhesion-preventive peritoneal surface was achieved by a mediator, CD44, in menstrual blood and that the ability of endometriotic cells to invade, induced by MMP, was achieved through up-regulation of MMP activity by the mediator tenascin.

Tumor Necrosis Factor-α and Interleukin-1β Treatment of Endometrial Stromal Cells Does not Promote Their Adhesion to Peritoneal Mesothelial Cells in an in Vitro Model of Early-Stage Endometriosis

In this study, we developed an original and reproducible quantitative in vitro model of endometrial cell adhesion to peritoneal mesothelial cells in order to better assess the impact of pro-inflammatory cytokines on early-stage endometriosis development. We demonstrated that pre-treatment with TNF-α and IL-1β does not promote endometrial stromal cell adhesion to peritoneal mesothelial cells.