scholarly journals Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis

Reproduction ◽  
2020 ◽  
Author(s):  
Yingying Zhou ◽  
Yangying Peng ◽  
Qingqing Xia ◽  
Dewen Yan ◽  
Huiping Zhang ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Endometrial Receptivity ◽  
Indian Hedgehog ◽  
Marker Protein ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Molecule Inhibitor ◽  
Gynecological Diseases ◽  
Autophagic Activity

Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small molecule inhibitor, GANT61, or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by the LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.

Inhibition of TMEM16A impedes embryo implantation and decidualization in mice

Reproduction ◽  
2018 ◽  
Author(s):  
Qianrong Qi ◽  
Yifan Yang ◽  
Kailin Wu ◽  
Qingzhen Xie
Keyword(s):  
Progesterone Receptor ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Mouse Uterus ◽  
Endometrial Stromal Cells ◽  
Uterine Endometrium ◽  
Molecule Inhibitor ◽  
Pathway Inhibition ◽  
And Function ◽  
Reproductive Processes

Recent studies revealed that TMEM16A is involved in several reproductive processes, including ovarian estrogen secretion and ovulation, sperm motility and acrosome reaction, fertilization, and myometrium contraction. However, little is known about the expression and function of TMEM16A in embryo implantation and decidualization. In this study, we focused on the expression and regulation of TMEM16A in mouse uterus during early pregnancy. We found that TMEM16A is up-regulated in uterine endometrium in response to embryo implantation and decidualization. Progesterone treatment could induce TMEM16A expression in endometrial stromal cells through progesterone receptor/c-Myc pathway, which is blocked by progesterone receptor antagonist or the inhibitor of c-Myc signaling pathway. Inhibition of TMEM16A by small molecule inhibitor (T16Ainh-A01) resulted in impaired embryo implantation and decidualization in mice. Treatment with either specific siRNA of Tmem16a or T16Ainh-A01 inhibited the decidualization and proliferation of mouse endometrial stromal cells. In conclusion, our results revealed that TMEM16A is involved in embryo implantation and decidualization in mice, compromised function of TMEM16A may lead to impaired embryo implantation and decidualization.

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.

scholarly journals Bovine herpesvirus 4 is tropic for bovine endometrial cells and modulates endocrine function

Reproduction ◽  
2007 ◽  
Vol 134 (1) ◽  
pp. 183-197 ◽  
Author(s):  
Gaetano Donofrio ◽  
Shan Herath ◽  
Chiara Sartori ◽  
Sandro Cavirani ◽  
Cesidio Filippo Flammini ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Stromal Cells ◽  
Bovine Herpesvirus ◽  
Endocrine Function ◽  
Uterine Disease ◽  
Endometrial Stromal Cells ◽  
Persistently Infected ◽  
Endometrial Cells ◽  
Bovine Herpesvirus 4 ◽  
Herpesvirus 4

Bovinepostpartumuterine disease, metritis, affects about 40% of animals and is widely considered to have a bacterial aetiology. Although the γ-herpesvirus bovine herpesvirus 4 (BoHV-4) has been isolated from several outbreaks of metritis or abortion, the role of viruses in endometrial pathology and the mechanisms of viral infection of uterine cells are often ignored. The objectives of the present study were to explore the interaction, tropism and outcomes of BoHV-4 challenge of endometrial stromal and epithelial cells. Endometrial stromal and epithelial cells were purified and infected with a recombinant BoHV-4 carrying an enhanced green fluorescent protein (EGFP) expression cassette to monitor the establishment of infection. BoHV-4 efficiently infected both stromal and epithelial cells, causing a strong non-apoptotic cytopathic effect, associated with robust viral replication. The crucial step for the BoHV-4 endometriotropism appeared to be after viral entry as there was enhanced transactivation of the BoHV-4 immediate early 2 gene promoter following transient transfection into the endometrial cells. Infection with BoHV-4 increased cyclooxygenase 2 protein expression and prostaglandin estradiol secretion in endometrial stromal cells, but not epithelial cells. Bovine macrophages are persistently infected with BoHV-4, and co-culture with endometrial stromal cells reactivated BoHV-4 replication in the persistently infected macrophages, suggesting a symbiotic relationship between the cells and virus. In conclusion, the present study provides evidence of cellular and molecular mechanisms, supporting the concept that BoHV-4 is a pathogen associated with uterine disease.

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.

Seminal plasma enhances and accelerates progesterone-induced decidualisation of human endometrial stromal cells

2012 ◽  
Vol 24 (3) ◽  
pp. 517 ◽  
Author(s):  
U. Doyle ◽  
N. Sampson ◽  
C. Zenzmaier ◽  
P. Schwärzler ◽  
P. Berger
Keyword(s):  
Seminal Plasma ◽  
Stromal Cells ◽  
Prolonged Exposure ◽  
Embryo Implantation ◽  
Combined Treatment ◽  
Morphological Differentiation ◽  
Endometrial Receptivity ◽  
Limiting Factor ◽  
Mrna Levels ◽  
Endometrial Stromal Cells

In preparation for embryo implantation, endometrial stromal cells (ESC) undergo differentiation, termed decidualisation. Enhancing endometrial decidualisation may overcome reduced endometrial receptivity, a major limiting factor in natural and assisted reproduction. To determine whether seminal plasma (SP) influences decidualisation, primary human ESC were treated with progesterone (P4, 50 ng mL–1) in the presence or absence of dialysed SP (0.5%) for 24 h or for up to 27 days to investigate immediate early effects or the effects of prolonged exposure, respectively. Combined SP and P4 treatment induced ESC morphological differentiation. Relative to control, P4 alone, and SP alone combined treatment with SP and P4 for 27 days significantly upregulated mRNA levels of the decidua-specific markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP1). Consistently, PRL protein secretion was significantly increased over the course of 27 days combined SP and P4 treatment relative to control, P4 alone and SP alone. Likewise, IGFBP1 secretion was significantly greater relative to control and P4 alone over the course of 27 days. Thus, SP enhances and accelerates P4-mediated decidualisation of human ESC and may enhance endometrial receptivity.

scholarly journals Indoleamine 2,3-dioxygenase suppresses the cytotoxicity of 1 NK cells in response to ectopic endometrial stromal cells in endometriosis

Reproduction ◽  
2018 ◽  
Author(s):  
Xuan-Tong Liu ◽  
Hui-Ting Sun ◽  
Zhong-Fang Zhang ◽  
Ru-Xia Shi ◽  
Li-Bing Liu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Stromal Cells ◽  
Therapeutic Strategy ◽  
Neutralizing Antibody ◽  
Inhibitory Effect ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Indoleamine 2,3 Dioxygenase ◽  
Healthy Control

It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK. Co-culture with endometrial stromal cells (nESCs) from healthy control or ectopic ESCs (eESCs) from women with EMS led to a significant increase in the IDO level in NK cells from peripheral blood, particularly eESCs, and an anti-TGF-β neutralizing antibody suppressed these effects in vitro. NK cells co-cultured with ESC more preferentially inhibited the viability of nESCs than eESCs did, and pretreating with 1-methyl-tryptophan (1-MT), an IDO inhibitor, reversed the inhibitory effect of NK cells on eESC viability. These data suggest that ESCs induce IDO+NK cells differentiation partly by TGF-β, and that IDO further restricts the cytotoxicity of NK cells in response to eESCs, which provides a potential therapeutic strategy for EMS patients, particularly those with a high number of impaired cytotoxic IDO+NK cells.

scholarly journals GZFLW Induces Apoptosis of Ectopic Endometrial Stromal Cells via Promoting VPS53 Protein Stability

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Ziyu Zhang ◽  
Faying Liu ◽  
YunYun Xu ◽  
Huang Huang ◽  
Yang Zou ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Stromal Cells ◽  
In Vitro Study ◽  
Absolute Quantification ◽  
Endometrial Stromal Cells ◽  
Gynecological Diseases ◽  
Isobaric Tags ◽  
Differential Expression Protein ◽  
Vacuolar Protein

Endometriosis is still a major problem in obstetrics and gynecology. While GZFLW (Gui Zhi Fu Ling Wan) has been originally used for treating gynecological diseases, however, the molecular mechanism that GZFLW acts on endometriosis is not clear. To investigate the molecular mechanism that GZFLW plays role on endometriosis, iTRAQ (isobaric tags for relative and absolute quantification) proteomics and human endometrial stromal cells (Y14) obtained from a patient with endometriosis were used in in vitro study. Our results demonstrated that GZFLW decreased Y14 cells proliferation while increased cells apoptosis. The differential expression protein VPS53 (Vacuolar protein sorting 53 homolog) was predicted by iTRAQ coupled LC-MS/MS and further identified by western blot. Besides, GZFLW induced VPS53 protein level by promoting its stabilization. Our findings highlight a novel role for VPS53 in gynecology and provide a potent therapeutic strategy against endometriosis.

scholarly journals Decorin induced by progesterone plays a crucial role in suppressing endometriosis

2014 ◽  
Vol 223 (2) ◽  
pp. 203-216 ◽  
Author(s):  
Yoshihiro Joshua Ono ◽  
Yoshito Terai ◽  
Akiko Tanabe ◽  
Atsushi Hayashi ◽  
Masami Hayashi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mrna Expression ◽  
Cell Lines ◽  
Stromal Cells ◽  
Crucial Role ◽  
Dependent Manner ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Cycle Arrest ◽  
Dose Dependent

Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on the in vitro proliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examined DCN mRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed that DCN mRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.

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