Altered retinoid signaling compromises decidualization in human endometriotic stromal cells

Reproduction ◽  
2017 ◽  
Vol 154 (3) ◽  
pp. 207-216 ◽  
Author(s):  
Mary Ellen Pavone ◽  
Saurabh Malpani ◽  
Matthew Dyson ◽  
Serdar E Bulun
Keyword(s):  
Stromal Cells ◽  
Embryo Implantation ◽  
Carrier Protein ◽  
Normal Endometrium ◽  
Endometrial Stromal Cells ◽  
Paracrine Factors ◽  
Endometrial Cells ◽  
Retinoid Signaling ◽  
The Media ◽  
Metabolizing Enzyme

Decidualization alters multiple molecular pathways in endometrium to permit successful embryo implantation. We have reported that paracrine factors, including retinoids, secreted from progesterone-treated endometrial stromal cells, act on nearby epithelial cells to induce the estradiol metabolizing enzyme HSD17B2. This same induction is not seen in endometriotic stromal cells. We have also shown significant differences in retinoid uptake, metabolism and action in endometriotic tissue and stromal cells compared to normal endometrium. Here, we characterize retinoid signaling during decidualization in these cells. Endometrial and endometriotic cells were isolated, cultured and incubated and decidualized. Genes involved in retinoid metabolism and trafficking were examined using RT-PCR and Western blotting. Prolactin, a decidualization marker, was also examined. We found that both endometrial and endometriotic stromal cells express all intracellular proteins involved in retinoid uptake and metabolism. Decidualization significantly reduced the expression of the genes responsible for retinoid uptake and shuttling to the nucleus. However, expression of CRBP1, an intracellular carrier protein for retinol, increased, as did RBP4, a carrier protein for retinol in the blood, which can function in a paracrine manner. Secreted RBP4 was detected in the media from decidualized endometrial cells but not from endometriotic cells. We believe that retinoid trafficking in endometrial stromal cells during decidualization may shift to favor paracrine rather than intracrine signaling, which may enhance signaling to the adjacent epithelium. There is blunting of this signaling in endometriotic cells. These alterations in retinoid signaling may help explain the decidualization defects and deficient estradiol inactivation (via HSD17B2) seen in endometriosis.

scholarly journals Immunosuppressive Factor MNSFβ Regulates Cytokine Secretion by Mouse Lymphocytes and Is Involved in Interactions between the Mouse Embryo and Endometrial Cells In Vitro

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Yaping He ◽  
Zhaogui Sun ◽  
Yan Shi ◽  
Yahong Jiang ◽  
Zhefu Jia ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Embryo Implantation ◽  
Cytokine Secretion ◽  
Embryonic Cells ◽  
Suppressor Factor ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Coculture Model ◽  
Mouse Lymphocytes

Immune tolerance at the fetomaternal interface must be established during the processes of implantation and pregnancy. Monoclonal nonspecific suppressor factor beta (MNSFβ) is a secreted protein that possesses antigen-nonspecific immune-suppressive function. It was previously reported that intrauterine immunoneutralization of MNSFβ significantly inhibited embryo implantation in mice. In the present study, MNSFβ protein expression was up- or downregulated by overexpression or RNA interference, respectively, in HCC-94 cells and the culture supernatants used to determine effects of MNSFβ on the secretion of IL-4 and TNFα from mouse lymphocytes as detected by ELISA. A coculture model of mouse embryos and endometrial stromal cells was also utilized to determine the effects of a specific anti-MNSFβ antibody on hatching and growth of embryos in vitro. The results show that MNSFβ induced secretion of IL-4 and inhibited secretion of TNFα from mouse lymphocytes. Following immunoneutralization of MNSFβ protein in the HCC-94 supernatant, the stimulatory effect of MNSFβ on IL-4 secretion from mouse lymphocytes was reduced, while the inhibitory effect on secretion of TNFα was abrogated. Expression of MNSFβ was detected in both embryonic and endometrial stromal cells, and its immunoneutralization inhibited the hatching and spreading of embryos in an in vitro coculture model. These results indicated that MNSFβ may play critical roles during the peri-implantation process by regulating cytokine secretion of lymphocytes and by mediating the crosstalk between embryonic cells and endometrial stromal cells.

Decreased mixed lineage leukemia 1 is involved in endometriosis-related infertility

2021 ◽  
Vol 66 (1) ◽  
pp. 45-57
Author(s):  
Xue Wen ◽  
Yao Xiong ◽  
Huimin Liu ◽  
Ting Geng ◽  
Ling Jin ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Stromal Cells ◽  
Expression Patterns ◽  
Embryo Implantation ◽  
Hypoxia Inducible Factor ◽  
Gene Promoter ◽  
Mixed Lineage Leukemia ◽  
Normal Endometrium ◽  
Endometrial Stromal Cells

The aberrant histone methylation patterns contribute to the pathogenesis of endometriosis (EM). Mixed lineage leukemia 1 (MLL1), a histone methyltransferase, is crucial for gene expression by catalyzing the trimethylation of histone 3 lysine 4 (H3K4me3) in gene promoter. This study aimed to explore whether MLL1 is involved in EM-related infertility. The expressions of MLL1 and H3K4me3 were analyzed in the eutopic endometria from EM women with infertility (n = 22) and the normal endometria from EM-free women (n = 22). Mouse EM model was established. The MLL1 and H3K4me3 expression patterns in mice endometria of early pregnancy were also investigated. Immortalized human endometrial stromal cells (iESCs) were cultured and underwent in vitro decidualization. The chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) was performed to find the target gene of MLL1 during decidual process. Results showed that both MLL1 and H3K4me3 decreased in the eutopic endometrium from EM patients compared to that in the normal endometrium. During early pregnancy and the decidual process, MLL1 and H3K4me3 were significantly upregulated in stromal cells. ChIP-seq and ChIP-qPCR found that the cytochrome c oxidase subunit 4I 2 (COX4I2) was directly targeted by MLL1. The dominance of COX4I2-containing enzyme induced the expression of hypoxia-inducible factor-2α (HIF-2α), whose expression in the peri-implantation endometrium is essential for embryo implantation. Further results showed that MLL1 was directly regulated by progesterone (P4) – P4 receptors (PRs). Our study proved that MLL1 was involved in EM-related infertility, which may provide a novel approach to treat the nonreceptive endometrium in EM patients.

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.

scholarly journals Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010018
Author(s):  
Jianghong Cheng ◽  
Jia Liang ◽  
Yingzhe Li ◽  
Xia Gao ◽  
Mengjun Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Endometrial Stromal Cells ◽  
Conditional Deletion ◽  
Enhancer Binding Protein ◽  
Epithelial Remodeling ◽  
Multiple Signaling ◽  
Transcription 3

Approximately 75% of failed pregnancies are considered to be due to embryo implantation failure or defects. Nevertheless, the explicit signaling mechanisms governing this process have not yet been elucidated. Here, we found that conditional deletion of the Shp2 gene in mouse uterine stromal cells deferred embryo implantation and inhibited the decidualization of stromal cells, which led to embryonic developmental delay and to the death of numerous embryos mid-gestation, ultimately reducing female fertility. The absence of Shp2 in stromal cells increased the proliferation of endometrial epithelial cells, thereby disturbing endometrial epithelial remodeling. However, Shp2 deletion impaired the proliferation and polyploidization of stromal cells, which are distinct characteristics of decidualization. In human endometrial stromal cells (hESCs), Shp2 expression gradually increased during the decidualization process. Knockout of Shp2 blocked the decidual differentiation of hESCs, while Shp2 overexpression had the opposite effect. Shp2 knockout inhibited the proliferation of hESCs during decidualization. Whole gene expression profiling analysis of hESCs during the decidualization process showed that Shp2 deficiency disrupted many signaling transduction pathways and gene expression. Analyses of hESCs and mouse uterine tissues confirmed that the signaling pathways extracellular regulated protein kinases (ERK), protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3) and their downstream transcription factors CCAAT/enhancer binding protein β (C/EBPβ) and Forkhead box transcription factor O1 (FOXO-1) were involved in the Shp2 regulation of decidualization. In summary, these results demonstrate that Shp2 plays a crucial role in stromal decidualization by mediating and coordinating multiple signaling pathways in uterine stromal cells. Our discovery possibly provides a novel key regulator of embryo implantation and novel therapeutic target for pregnancy failure.

P–322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunj. Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings: The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number Not applicable

Inhibition of METTL3/m6A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosis

2021 ◽  
Author(s):  
Xiaoou Li ◽  
Wenqian Xiong ◽  
Xuefeng Long ◽  
Xin Dai ◽  
Yuan Peng ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Cellular Migration ◽  
Migration And Invasion ◽  
Diagnostic Biomarker ◽  
Rna Modifications ◽  
Normal Endometrium ◽  
Endometrial Stromal Cells ◽  
Ectopic Endometrium

Abstract N6-methyladenosine (m6A), one of the most abundant RNA modifications, is involved in the progression of many diseases, but its role and related molecular mechanisms in endometriosis remain unknown. To address these issues, we detected m6A levels in normal, eutopic and ectopic endometrium and found the m6A levels decreased in eutopic and ectopic endometrium compared with normal endometrium. In addition, we proved that methyltransferase-like 3 (METTL3) downregulation accounted for m6A reduction in endometriosis. Furthermore, we observed that METTL3 knockdown facilitated the migration and invasion of human endometrial stromal cells (HESCs), while METTL3 overexpression exerted opposite effects, suggesting that METTL3 downregulation might contribute to endometriosis development by enhancing cellular migration and invasion. Mechanistically, METTL3-dependent m6A was involved in the DGCR8-mediated maturation of primary microRNA126 (miR126, pri-miR126). Moreover, miR126 inhibitor significantly enhanced the migration and invasion of METTL3-overexpressing HESCs, whereas miR126 mimics attenuated the migration and invasion of METTL3-silenced HESCs. Our study revealed the METTL3/m6A/miR126 pathway, whose inhibition might contribute to endometriosis development by enhancing cellular migration and invasion. It also showed that METTL3 might be a novel diagnostic biomarker and therapeutic target for endometriosis.

P-322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunja Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number not applicable

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.

Sign in / Sign up

Export Citation Format

Share Document