scholarly journals Expression of Matrix Metalloproteinases and Their Inhibitors in Endometrium: High Levels in Endometriotic Lesions

2020 ◽  
Vol 21 (8) ◽  
pp. 2840
Author(s):  
Alice Luddi ◽  
Camilla Marrocco ◽  
Laura Governini ◽  
Bianca Semplici ◽  
Valentina Pavone ◽  
...  
Keyword(s):  
Gene Expression ◽  
Matrix Metalloproteinases ◽  
Molecular Mechanisms ◽  
Uterine Cavity ◽  
Molecular Profile ◽  
Deep Infiltrating Endometriosis ◽  
Matrix Remodeling ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium ◽  
Endometrial Cells

Endometriosis is a condition defined as presence of endometrium outside of the uterine cavity. These endometrial cells are able to attach and invade the peritoneum or ovary, thus forming respectively the deep infiltrating endometriosis (DIE) and the ovarian endometrioma (OMA), the ectopic lesions feature of this pathology. Endometriotic cells display high invasiveness and share some features of malignancy with cancer cells. Indeed, the tissue remodeling underlining lesion formation is achieved by matrix metalloproteinases (MMPs) and their inhibitors. Therefore, these molecules are believed to play a key role in development and pathogenesis of endometriosis. This study investigated the molecular profile of metalloproteinases and their inhibitors in healthy (n = 15) and eutopic endometrium (n = 19) in OMA (n = 10) and DIE (n = 9); moreover, we firstly validated the most reliable housekeeping genes allowing accurate gene expression analysis in these tissues. Gene expression, Western blot, and immunofluorescence analysis of MMP2, MMP3, and MMP10 and their tissue inhibitors TIMP1 and TIMP2 demonstrated that these enzymes are finely tuned in these tissues. In OMA lesions, all the investigated MMPs and their inhibitors were significantly increased, while DIE expressed high levels of MMP3. Finally, in vitro TNFα treatment induced a significant upregulation of MMP3, MMP10, and TIMP2 in both healthy and eutopic endometrial stromal cells. This study, shedding light on MMP and TIMP expression in endometriosis, confirms that these molecules are altered both in eutopic endometrium and endometriotic lesions. Although further studies are needed, these data may help in understanding the molecular mechanisms involved in the extracellular matrix remodeling, a crucial process for the endometrial physiology.

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.

Impaired Localization of Claudin-11 in Endometriotic Epithelial Cells Compared to Endometrial Cells

2018 ◽  
Vol 26 (9) ◽  
pp. 1181-1192 ◽  
Author(s):  
Fabian Horné ◽  
Raimund Dietze ◽  
Eniko Berkes ◽  
Frank Oehmke ◽  
Hans-Rudolf Tinneberg ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tight Junctions ◽  
Cell Lines ◽  
Human Cancer ◽  
Deep Infiltrating Endometriosis ◽  
Endometrial Cell ◽  
Ovarian Endometriosis ◽  
Eutopic Endometrium ◽  
Endometrial Cells ◽  
Ectopic Endometrium

Claudins are the major components of tight junctions and are often deregulated in human cancer, permitting escape of cancer cells along with the acquisition of invasive properties. Similarly, endometrial cells also show invasive capabilities; however, the role of tight junctions in endometriosis has only rarely been examined. In this study, we analyzed the protein expression and localization of claudin-7 and claudin-11 in human eutopic and ectopic endometrium and endometrial cell lines. We identified claudin-7 primarily at the basolateral junctions of the glandular epithelial cells in eutopic endometrium as well as in the ectopic lesions in nearly all glands and cysts. Quantification of claudin-7 localization by HSCORE showed a slight increase in peritoneal and deep infiltrating endometriosis (DIE) compared to eutopic endometrium. In contrast, claudin-11 was localized mainly in the apicolateral junctions in nearly all glandular epithelial cells of the eutopic endometrium. Interestingly, we observed a deregulation of claudin-11 localization to a basal or basolateral localization in ovarian ( P < .001), peritoneal ( P < .01), and DIE ( P < .05) and a moderately decreased abundance in ovarian endometriosis. In endometrial cell lines, claudin-7 was only present in epithelial Ishikawa cells, and silencing by small-interfering RNA increased cell invasiveness. In contrast, claudin-11 could be demonstrated in Ishikawa and endometriotic 12Z and 49Z cells. Silencing of claudin-11 decreased invasiveness of 12Z slightly but significantly in 49Z. We suggest that although claudin-7 and claudin-11 can be found in nearly all eutopic and ectopic epithelial cells, the impaired localization of claudin-11 in ectopic endometrium might contribute to the pathogenesis of endometriosis.

scholarly journals Insight into Molecular Profile Changes after Skeletal Muscle Contusion Using Microarray and Bioinformatics Analyses

2020 ◽  
Author(s):  
Na Li ◽  
Ru-feng Bai ◽  
Chun Li ◽  
Li-hong Dang ◽  
Qiu-xiang Du ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Healing Process ◽  
Differentially Expressed ◽  
Molecular Profile ◽  
Wound Age ◽  
Functional Modules

Abstract Background: Muscle trauma frequently occurs in daily life. However, the molecular mechanisms of muscle healing, which partly depend on the extent of the damage, are not well understood. This study aimed to investigate gene expression profiles following mild and severe muscle contusion, and to provide more information about the molecular mechanisms underlying the repair process.Methods: A total of 33 rats were divided randomly into control (n = 3), mild contusion (n = 15), and severe contusion (n = 15) groups; the contusion groups were further divided into five subgroups (1, 3, 24, 48, and 168 h post-injury; n = 3 per subgroup). Then full genome microarray of RNA isolated from muscle tissue was performed to access the gene expression changes during healing process.Results: A total of 2,844 and 2,298 differentially expressed genes were identified in the mild and severe contusion groups, respectively. The analysis of the overlapping differentially expressed genes showed that there are common mechanisms of transcriptomic repair of mild and severe contusion within 48 h post-contusion. This was supported by the results of principal component analysis, hierarchical clustering, and weighted gene co‐expression network analysis of the 1,620 coexpressed genes in mildly and severely contused muscle. From these analyses, we discovered that the gene profiles in functional modules and temporal clusters were similar between the mild and severe contusion groups; moreover, the genes showed time-dependent patterns of expression, which allowed us to identify useful markers of wound age. We then performed an analysis of the functions of genes (including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway annotation, and protein–protein interaction network analysis) in the functional modules and temporal clusters, and the hub genes in each module–cluster pair were identified. Interestingly, we found that genes downregulated within 24−48 h of the healing process were largely associated with metabolic processes, especially oxidative phosphorylation of reduced nicotinamide adenine dinucleotide phosphate, which has been rarely reported. Conclusions: These results improve our understanding of the molecular mechanisms underlying muscle repair, and provide a basis for further studies of wound age estimation.

PGE2 and thrombin induce myofibroblast transdifferentiation via activinA and CTGF in endometrial stromal cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Kazuya Kusama ◽  
Yuta Fukushima ◽  
Kanoko Yoshida ◽  
Mana Azumi ◽  
Mikihiro Yoshie ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Activin A ◽  
Tissue Growth ◽  
Marker Genes ◽  
Type I ◽  
Endometrial Stromal Cells ◽  
Mesenchymal Transition ◽  
Endometrial Cells

Abstract Endometriosis is characterized by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal hemorrhage 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, menstruation-related factors, PGE2 and thrombin, a PAR1 agonist (P/T) induced epithelial-mesenchymal transition (EMT) of endometrial cells under hypoxia. However, the molecular mechanisms by which P/T induce development of endometriosis have not been fully characterized. To investigate the effects of P/T, RNA extracted from endometrial stromal cells (ESCs) treated with P/T were subjected to RNA sequence analysis, and identified activin A, FOS, GATA2 as upregulated genes. Activin A increased the expression of connective tissue growth factor (CTGF) and mesenchymal marker genes in ESCs. CTGF induced the expression of fibrosis marker type I collagen, fibronectin, and α-smooth muscle actin (αSMA), indicating fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. In addition, activin A, FOS, GATA2, CTGF, and αSMA were localized in endometriosis lesions. Taken together, our data show that P/T induce changes resembling EMT and FMT in ectopic ESCs derived from retrograde menstruation, and that these are associated with fibrotic changes in the lesions. Pharmacological means that block P/T-induced activin A and CTGF signaling may be strategies to inhibit fibrosis in endometriotic lesions.

scholarly journals Estradiol promotes cells invasion by activating β-catenin signaling pathway in endometriosis

Reproduction ◽  
2015 ◽  
Vol 150 (6) ◽  
pp. 507-516 ◽  
Author(s):  
Wenqian Xiong ◽  
Ling Zhang ◽  
Lan Yu ◽  
Wei Xie ◽  
Yicun Man ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Uterine Cavity ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium ◽  
T Cell Factor ◽  
17Β Estradiol ◽  
Enhancer Factor

Endometriosis is an estrogen-dependent disease that involves the adhesion, invasion, and angiogenesis of endometrial tissues outside of the uterine cavity. We hypothesized that a link exists between estrogen and beta-catenin (β-catenin) signaling in the pathogenesis of endometriosis. Human endometrial stromal cells (HESCs) were separated from eutopic endometrial tissues that were obtained from patients with endometriosis. β-catenin expression and cells invasiveness ability were up-regulated by 17β-estradiol (E2) in an estrogen receptor (ESR)-dependent manner, whereas β-catenin siRNA abrogated this phenomenon. Moreover, co-immunoprecipitation and dual immunofluorescence studies confirmed ESR1, β-catenin, and lymphoid enhancer factor 1/T cell factor 3 co-localization in the nucleus in HESCs after E2 treatment. To determine the role of β-catenin signaling in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium from endometriosis patients into ovariectomized severe combined immunodeficiency mice. The implantation of the endometrium was suppressed by β-catenin siRNA. Collectively, studies regarding β-catenin signaling are critical for improving our understanding of the pathogenesis of estrogen-induced endometriosis, which can translate into the development of treatments and therapeutic strategies for endometriosis.

Factor XII gene expression in endometrial stromal cells during decidualisation

2009 ◽  
Vol 21 (7) ◽  
pp. 840 ◽  
Author(s):  
Hiroaki Kawato ◽  
Tsutomu Tabata ◽  
Hiroyuki Minoura ◽  
Nao Murabayashi ◽  
Ning Ma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stromal Cells ◽  
Molecular Mechanisms ◽  
Human Embryos ◽  
Factor Xii ◽  
Kinin System ◽  
Endometrial Stromal Cells ◽  
Weak Expression ◽  
Secretory Endometrium

Decidualisation of endometrial stromal cells (ESC) is a prerequisite for the implantation of human embryos. Identification of genes that are upregulated or downregulated during decidualisation could lead to a better understanding of the molecular mechanisms involved in this process. In the present study, we examined differences in gene expression between decidualised and non-decidualised cells using microarray analysis and found that Factor XII (FXII) gene expression was upregulated during decidualisation. Furthermore, we also examined the expression of FXII by human ESC before and during pregnancy, as well as its expression by cells that had undergone decidualisation in vitro. Weak expression of FXII mRNA was detected in the non-pregnant endometrium that increased gradually from the proliferative to the secretory endometrium. During pregnancy, FXII mRNA expression was markedly increased in decidualised endometrium. When sex steroids (200 pg mL–1 of 17β-oestradiol and 100 ng mL–1 of progesterone) were used to induce in vitro decidualisation of ESC, the expression of FXII mRNA increased by approximately 25.3-fold compared with that in non-decidualised ESC. Using western blotting, we confirmed the presence of FXII protein (80 kDa) in ESC after in vitro decidualisation. Increased expression of FXII in ESC during decidualisation suggests that the kallikrein–kininogen–kinin system may be activated during the implantation of human embryos.

scholarly journals Epithelial–Mesenchymal Transition in Endometriosis—When Does It Happen?

2020 ◽  
Vol 9 (6) ◽  
pp. 1915 ◽  
Author(s):  
Lutz Konrad ◽  
Raimund Dietze ◽  
Muhammad A. Riaz ◽  
Georgios Scheiner-Bobis ◽  
Judith Behnke ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Deep Infiltrating Endometriosis ◽  
Intermediate Cell ◽  
Eutopic Endometrium ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Gradual Loss ◽  
Cell Remodeling ◽  
Epithelial Phenotype

Epithelial–mesenchymal transition (EMT) is an important process of cell remodeling characterized by the gradual loss of the epithelial phenotype and progressive gain of a mesenchymal phenotype. EMT is not an all-or-nothing process, but instead a transition of epithelial to mesenchymal cells with intermediate cell states. Recently, EMT was described in endometriosis, and many EMT-specific pathways like Twist, Snail, Slug, Zinc finger E-box-binding homeobox 1/2 (ZEB1/2), E/N-cadherin, keratins, and claudins are involved. However, as pointed out in this review, a comparison of the eutopic endometrium of women with and without endometriosis yielded only subtle changes of these EMT markers. Furthermore, only very few alterations in cell–cell contacts could be found but without changes in the epithelial phenotype. This suggests only a partial EMT which is not a prerequisite for the detachment of endometrial cells and, thus, not critical for the first step(s) in the pathogenesis of endometriosis. In contrast, the majority of changes in the EMT-related marker expression were found in the ectopic endometrium, especially in the three endometriotic entities, ovarian, peritoneal, and deep infiltrating endometriosis (DIE), compared with the eutopic endometrium. In this review, we examine the most important EMT pathways described in endometriosis and propose that partial EMT might result from the interaction of endometrial implants with their surrounding microenvironment.

scholarly journals Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 749
Author(s):  
Agnieszka Koppolu ◽  
Radosław B. Maksym ◽  
Wiktor Paskal ◽  
Marcin Machnicki ◽  
Beata Rak ◽  
...  
Keyword(s):  
Uterine Cavity ◽  
Genetic Alterations ◽  
Deep Infiltrating Endometriosis ◽  
Driver Genes ◽  
Kras Mutations ◽  
Deep Endometriosis ◽  
Eutopic Endometrium ◽  
Cancer Driver ◽  
Cancer Driver Genes ◽  
Custom Panel

Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

scholarly journals BMSCs and Pectin-Based E2-Loaded Microcapsules with Injectable Pectin-Pluronic® F-127 Scaffolds for Mouse Endometrial Regeneration Application

2021 ◽  
Author(s):  
Yuelin Wu ◽  
Shengyi Gu ◽  
Jonathan M. Cobb ◽  
Griffin H. Dunn ◽  
Taylor A. Muth ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Basal Layer ◽  
Uterine Cavity ◽  
Stem Cell Differentiation ◽  
Functional Layer ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Endometrial Injury ◽  
Differentiation And Proliferation ◽  
Endometrial Regeneration

Abstract Background Uterine endometrium is a highly dynamic tissue which consists of a basal layer and a functional layer. Bone marrow-derived mesenchymal stem cells (BMSCs) have been recognized as new candidates for the treatment of serious endometrial injuries. However, due to the local microenvironment of damaged endometrium, transplantation of BMSCs yielded disappointing results with respect to survival, attachment, differentiation, and proliferation. Methods Pectin-Pluronic® F-127 scaffolds were fabricated. E2 was encapsulated into the W/O/W microspheres to construct pectin-based E2-loaded microcapsules (E2 MPs). The BMSCs/E2 MPs/scaffolds system was then injected into the uterine cavity of mouse endometrial injury model. Furthermore, the mechanism of E2 in promoting the repair of endometrial injury was also investigated. Result Pectin-Pluronic® F-127 scaffolds could provide three-dimensional architecture for the attachment, growth, and migration of BMSCs. E2 MPs has the potential to serve as a long-term reliable source of E2 for endometrial regeneration. At four weeks after transplantation, it was demonstrated that the system increased proliferative abilities of uterine endometrial cells, facilitated microvasculature regeneration, and restored the ability of endometrium to receive an embryo, suggesting that the BMSCs/E2 MPs/scaffolds system is a promising treatment option for endometrial regeneration. Exosomes are critical paracrine mediators that act as biochemical cues to direct stem cell differentiation. In this study, it was found that the expression of endometrial epithelial cells (EECs) markers was up-regulated in BMSCs treated by exosomes secreted from endometrial stromal cells (ESCs-Exos). Exosomes derived from E2-stimulated ESCs further promoted the expression level of EECs markers in BMSCs, suggesting exosomes released from ESCs by E2 stimulation could enhance the differentiation efficiency of BMSCs. Conclusion The BMSCs/E2 MPs/scaffolds therapeutic strategy may be beneficial in the treatment of severely damaged endometrium. Exosomes derived from ESCs play paracrine roles in endometrial regeneration stimulated by E2, potentially modulating the differentiation of BMSCs.

scholarly journals Identification of distinct transcriptome signatures of human adipose tissue from fifteen depots

2020 ◽  
Vol 28 (12) ◽  
pp. 1714-1725
Author(s):  
Dorit Schleinitz ◽  
Kerstin Krause ◽  
Tobias Wohland ◽  
Claudia Gebhardt ◽  
Nicolas Linder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Human Adipose Tissue ◽  
Matrix Remodeling ◽  
Fat Depots

AbstractThe functional and metabolic characteristics of specific adipose tissue (AT) depots seem to be determined by intrinsic mechanisms. We performed a comprehensive transcriptome profiling of human AT from distinct fat depots to unravel their unique features potentially explaining molecular mechanisms underlying AT distribution and their contribution to health and disease. Post-mortem AT samples of five body donors from 15 anatomical locations were collected. Global mRNA expression was measured by Illumina® Human HT-12 v4 Expression BeadChips. Data were validated using qPCR and Western Blot in a subset of ATs from seven additional body donors. Buccal and heel AT clearly separated from the “classical” subcutaneous AT depots, and perirenal and epicardial AT were distinct from visceral depots. Gene-set enrichment analyses pointed to an inflammatory environment and insulin resistance particularly in the carotid sheath AT depot. Moreover, the epicardial fat transcriptome was enriched for genes involved in extracellular matrix remodeling, inflammation, immune signaling, coagulation, thrombosis, beigeing, and apoptosis. Interestingly, a striking downregulation of the expression of leptin receptor was found in AT from heel compared with all other AT depots. The distinct gene expression patterns are likely to define fat depot specific AT functions in metabolism, energy storage, immunity, body insulation or as cushions. Improved knowledge of the gene expression profiles of various fat depots may strongly benefit studies aimed at better understanding of the genetics and the pathophysiology of obesity and adverse body fat composition.

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