Changes In Endometrial Cells Research Articles

Epigenetic Landscapes of Endometriosis: From Pathogenesis to Precision Medicine

Endometriosis, a challenging gynecological disorder characterized by the ectopic presence of endometrial-like tissue, presents significant diagnostic and therapeutic hurdles due to its complex etiology and diverse clinical manifestations. Recent advancements in understanding its pathogenesis have underscored the pivotal role of epigenetic alterations, offering new insights into disease mechanisms and therapeutic targets. Epigenetic changes in endometrial cells significantly contribute to endometriosis pathogenesis, disrupting normal physiology and hormone responsiveness, particularly to progesterone. Dysregulation of histone modifications, DNA methylation, and non-coding RNA expression disrupts cellular homeostasis and promotes disease progression. Histone modifications, notably methylation and acetylation, influence chromatin structure and gene expression, affecting progesterone responsiveness and disease progression. Epigenetic regulators such as Cfp1 modulate progesterone receptor expression and downstream signalling pathways, presenting potential therapeutic targets. Non-coding RNAs, including miRNAs and lncRNAs, exert regulatory effects on gene expression and are implicated in endometriosis pathogenesis. Dysregulated expression disrupts cellular homeostasis and promotes disease progression. Biomarker studies have identified specific miRNAs and lncRNAs associated with endometriosis, offering avenues for non-invasive diagnosis and targeted therapies. siRNA-based therapies targeting key genes involved in endometriosis pathogenesis show promise as novel treatment modalities. By modulating gene expression and cellular functions, siRNA-based therapies offer a targeted approach to mitigate pathological processes. In this review, we summarize recent findings in the molecular mechanisms and regulatory pathways of endometriosis, offering valuable insights into pathology and therapeutic interventions. Future research efforts aimed at elucidating the complex interplay between epigenetic regulators and disease pathways hold promise for innovative diagnostic tools and targeted therapies.

The Different Gene Expression Profile in the Eutopic and Ectopic Endometrium Sheds New Light on the Endometrial Seed in Endometriosis.

The changes in endometrial cells, both in the eutopic endometrium of patients with and without endometriosis and in lesions at ectopic sites, are frequently described and often compared to tumorigenesis. In tumorigenesis, the concept of "seed and soil" is well established. The seed refers to tumor cells with metastatic potential, and the soil is any organ or tissue that provides a suitable environment for the seed to grow. In this systematic review (PRISMA-S), we specifically compared the development of endometriosis with the "seed and soil" hypothesis. To determine changes in the endometrial seed, we re-analyzed the mRNA expression data of the eutopic and ectopic endometrium, paying special attention to the epithelial-mesenchymal transition (EMT). We found that the similarity between eutopic endometrium without and with endometriosis is extremely high (~99.1%). In contrast, the eutopic endometrium of patients with endometriosis has a similarity of only 95.3% with the ectopic endometrium. An analysis of EMT-associated genes revealed only minor differences in the mRNA expression levels of claudin family members without the loss of other cell-cell junctions that are critical for the epithelial phenotype. The array data suggest that the changes in the eutopic endometrium (=seed) are quite subtle at the beginning of the disease and that most of the differences occur after implantation into ectopic locations (=soil).

Effect of amber powder on endometrial ultrastructure and MAPK pathway in endometriosis model rats

Purpose: To explore the therapeutic role of amber powder in endometriosis by investigating its effect on endometrial ultrastructure, ERK1/2, p38MAPK, and NF-κB mRNA pathways and CSRC/EFR/ERK1/2 proteins.
 Methods: Sprague Dawley (SD) rats were randomly divided into blank group, disease model group (untreated), amber powder high-dose group, amber powder medium-dose group, amber powder lowdose group and danazol group. Morphological changes in endometrial cells were studied using transmission electron microscopy. The expression of ERK1/2, p38MAPK, and NF-κB mRNA in endometrial tissues of each group was determined using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was utilized for the measurement of C-SRC/EFR/ERK1/2 pathway protein expression.
 Results: The endometriosis rats treated with a high-, medium- and low-dose amber powder showed a decrease in the volume of ectopic lesions, compared with the untreated disease model group. The expressions of ERK1/2, p38MAPK, NF-κB mRNA, and C-SRC/EFR/ERK1/2 protein were higher in the eutopic and ectopic endometrial tissues in untreated disease group than those in normal control group. Moreover, treatment of endometriosis rats with amber powder revealed a reduction in the expressions of ERK1/2, p38MAPK, NF-κB mRNA and C-SRC/EFR/ERK1/2 proteins in eutopic and ectopic endometrium tissues.
 Conclusion: Amber powder reduces ectopic lesions and slows down the development of endometriosis, probably via inhibition of MAPK pathway genes in eutopic and ectopic endometrial tissues.

Endometrial epithelial–mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal haemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or oestrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

Shared Molecular Features Linking Endometriosis and Obstetric Complications

Recent epidemiological research has shown the increased risk of adverse pregnancy outcomes in women with endometriosis compared with the general population. The aim of this review is to explore common pathophysiologic mechanisms between endometriosis and obstetric complications. A computerized literature search was performed to identify relevant studies. The search covered the period between January 2008 and October 2018. One of the potential mechanisms driving the initiation and progression of endometriosis is the accumulation of a variety of epigenetic changes in endometrial cells. Epigenetic control of gene expression which is considered to be responsible for the development of endometriosis is commonly seen in patients with preeclampsia, small for gestational age (SGA), or preterm birth. DLX5 and GATA3, paternally imprinted genes, and CDKN1C, a maternally imprinted gene, were aberrantly expressed in placenta tissues of the preeclampsia; CDKN1C, the growth inhibitor gene, was upregulated in human SGA placentas; and hypomethylation of PTGER2 would be associated with preterm birth. Preeclampsia, SGA, or preterm birth may share common epigenetic alterations with endometriosis, which raises the possibility that the occurrence of two conditions might be nonrandom. To date, however, there is a lack of evidence that links endometriosis and other obstetric complications, such as postpartum hemorrhage or placental abruption, at the epigenetic level. In conclusion, epigenetic changes may be a common hallmark of two conditions: endometriosis and obstetrical complications, such as preeclampsia, SGA, or preterm birth.

Structural uterine changes in postpartum endometritis in cows.

Aim:The purpose of this work was to study the dynamics of structural manifestations of acute cases of postpartum endometritis in cows.Materials and Methods:The light and electron microscopy methods were used when studying structural changes in the endometrium in case of postpartum endometritis in seven cows. Sections of endometrial specimens for light microscopy, 5-7 µm thick, were stained with hematoxylin and eosin and also by Van Gieson’s. For electron microscopy, semi-thin sections were stained with Azur-2 in combination with basic fuchsin, as well as contrasting by lead citrate and uranyl acetate.Results:As a result of the study, we have established the following: Necrobiosis of the epithelial layer of the mucosa, cellular infiltration with shaped elements of blood in the functional layer, swelling of the cells of the uterine gland, and single microbial cells on the surface of the mucosa. We have noted edema of the stroma of the functional layer of the endometrium, swelling of the epithelial layer of the endometrial mucosa, and swelling of fibroblastic and lymphoid cells. Ultrastructural changes in endometrial cells in case of acute postpartum endometritis in cows are accompanied by the destruction of microvilli on the apical surface of the epithelium, an abundance of coccal microflora on the surface of the epithelium, necrobiosis of epithelial cells, and partial edema of the nucleus, and cytoplasm of the histiocyte.Conclusion:We had established that acute purulent-catarrhal dystrophic processes were observed in the structural organization of the endometrium. In the depth of catarrhal mucus on the surface of the endometrium, there was an abundance of bacterial flora, with diplococci being prevalent. In ultrastructural organization of the endometrium, we observed deep dystrophic and necrobiotic processes in the parenchyma and endometrial stroma, as well as exudative processes with a change in the integrity of the microcirculatory bed. Thus, to prevent an inflammatory process from turning into a latent form, it is necessary to detect acute postpartum endometritis promptly using diagnostic methods taking into account the obtained parameters of the dynamics of structural changes in the uterine tissues.

Ulipristal Acetate Interferes With Actin Remodeling Induced by 17β-Estradiol and Progesterone in Human Endometrial Stromal Cells.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator (SPRM) used for emergency contraception and for the medical management of symptomatic uterine fibroids (UF). Treatment with UPA turns in amenorrhea and UF volume reduction. Treatment with UPA is associated with the frequent development of benign, transitory endometrial changes known as SPRM-associated endometrial changes (PAECs). Why PAECs develop and their biological or cellular basis is unknown. Sex steroids, including estrogen and progesterone, are established modulators of the actin cytoskeleton in various cells, including endometrial cells. This explains several morphological and functional changes in endometrial cells. We thus hypothesized that UPA may alter the appearance of the endometrium by interfering with the actions of 17β-estradiol (E2) or progesterone (P4) on actin dynamics. We isolated and cultured human endometrial stromal cells (ESC) from endometrial biopsies from healthy fertile women. Treatment with E2 or P4 stimulated visible actin rearrangements with actin remodeling toward the membrane. Activation through phosphorylation of the actin regulatory proteins, Moesin, and focal adhesion kinase (FAK), hacked actin remodeling induced by E2 and P4. Membrane re-localization of Paxillin and Vinculin were also induced by E2 and P4, showing the formation of focal adhesion complexes. All these E2 and P4 actions were inhibited by co-treatment with UPA, which was otherwise inactive if given alone. The cytoskeletal changes induced by E2 and P4 turned into increased motility of ESC, and UPA again blocked the actions E2 and P4. In conclusion, we find that UPA interferes with the cytoskeletal actions of E2 and P4 in ESC. This finding helps understanding the mode of actions of SPRMs in the endometrium and may be relevant for other potential clinical applications of UPA.

Adipose-Derived VEGF-mTOR Signaling Promotes Endometrial Hyperplasia and Cancer: Implications for Obese Women.

Obesity is responsible for increased morbidity and mortality in endometrial cancer. Despite the positive correlation of body mass index (BMI) or obesity in endometrial carcinogenesis, the contribution of adipose tissue to the pathogenesis of endometrial hyperplasia and cancer is unclear. This study clarifies the role of adipocytes in the pathogenesis of endometrial cancer by demonstrating that adipocyte-conditioned medium (ACM) increases proliferation, migration, and survival of endometrial cancer cells compared with preadipocyte-conditioned medium (PACM). Comparative cytokine array analysis of ACM and PACM reveal upregulation of a group of cytokines belonging to the VEGF signaling pathway in ACM. VEGF protein expression is upregulated in visceral adipose tissue (VAT) in obese patients, which is correlated with increased tumor growth in an in vivo xenograft model. The increased tumor size is mechanistically associated with the activation of the PI3K/AKT/mTOR pathway, a downstream target of VEGF signaling, and its suppression decreased the growth-promoting effects of VAT on endometrial cancer cells. Similar to the human model systems, pathologic changes in endometrial cells in a hyperphagic obese mouse model are associated with increased body weight and hyperactive mTOR signaling. Analysis of human tissue specimens depicts increased in tumor vasculature and VEGF-mTOR activity in obese endometrial cancer patients compared with nonobese patients. Collectively, these results provide evidence that VEGF-mTOR signaling drives endometrial cell growth leading to hyperplasia and cancer.Implications: Adipocyte-derived VEGF-mTOR signaling may be an attractive therapeutic target against endometrial cancer in obese women. Mol Cancer Res; 16(2); 309-21. ©2017 AACR.

The knockdown of progesterone receptor isoform B (PR-B) promotes proliferation in immortalized endometrial stromal cells

The knockdown of PR-B by siRNA resulted in a significant increase in proliferation in an immortalized endometrial stromal cell line. This suggests that PR-B knockdown might be responsible, at least in part, for increased proliferation and resistance to apoptosis as seen in the eutopic and ectopic endometrium of women with endometriosis.

Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone

The potent antiproliferative effect of progestins has been utilized in clinical regimens for treatment of endometrial proliferative disorders. The progestin infiltrated intrauterine device used as therapy for endometrial carcinoma as well as endometrial hyperplasia yields a hundred-fold increase of local progestin concentration in the endometrium compared to that of oral treatment. The genetic basis for the complex effects of high dose progestins and the different signalling pathways regulated by these genes have never been accurately surveyed. The aim of the present study was to determine the gene expression pattern in highly differentiated endometrial cancer cells (Ishikawa) after short time exposure to high progesterone doses. In eight independent experiments, cells were treated with progesterone (30 μg/ml) for 4 h and gene expression was compared to that of untreated cells, which served as controls. Microarray analysis revealed 247 differentially expressed genes of which 126 were up-regulated and 121 were down-regulated. Of these, 135 genes are known to be involved in biological processes like cell cycle, cell proliferation and differentiation, developmental processes, immune responses, intracellular protein traffic and transport. Our study shows that microarray analysis can detect relevant gene expression changes in endometrial cells treated with progestin, including those involved in several alternative transcriptional factors and signalling pathways. Many of the differentially expressed genes were not previously known to be affected by progesterone or have unknown biological functions. Characterization of these genes may give new insights into molecular responses to treatment with high progesterone doses. Alternative signalling pathways for progesterone, rather than the classical steroid receptors pathways are also suggested.

The oestrous cycle and early pregnancy – a new concept of local endocrine regulation

Facts discovered in recent decades have compelled us to revise long-established views on the physiological regulation of cyclic adjustments to the reproductive system in preparation for pregnancy in females. Evidence has been presented to show that changes in the uterine blood supply induced by the oestrogen/progesterone ratio in the blood and cytokines are important in the regulation of the secretory function of the endometrium. Progressive reduction in uterine blood flow during the luteal phase of the oestrous cycle causes regressive changes in endometrial cells and release of prostaglandin (PG) F 2α, resulting in initiation of luteolysis. Retrograde transfer of PGF 2α in the area of the mesometrium vasculature is an important element in the mechanism protecting the corpora lutea against luteolysis before day 12 of the porcine oestrous cycle and during early pregnancy and pseudopregnancy. Results of many studies presented in this review indicate that PGF 2α pulses in uterine venous blood during the follicular phase of the oestrous cycle may not be due to PGF 2α secretion by endometrial cells, but occur due to remodeling of the endometrium and pulsatile exretion of PGF 2α in accordance with rhythmic uterine contractions caused by oxytocin.