Loss of miR-29a impairs decidualization of endometrial stromal cells by TET3 mediated demethylation of Col1A1 promoter.
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ABSTRACT:
SUBMITTER: Liu A
PROVIDER: S-EPMC8449092 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During the menstrual cycle, the endometrium undergoes cyclic changes of cellular proliferation, differentiation, and death, an essential preparation of the endometrium for its interaction with the implanting embryo. In particular, the differentiation of endometrial stromal cells, named decidualization, ensures the formation of a proper feto-maternal interface for a regulated trophoblast invasion and correct placental orientation and growth. Interestingly, autophagy, an intracellular degradation process of great importance for the maintenance of cellular homeostasis, plays an important role in cell proliferation, differentiation, and growth. In the endometrium, increased detection of autophagy markers correlates with the progression of the menstrual cycle. However, until now, it was unknown whether autophagy contributes to the proper function of the endometrium. In this study, we show that autophagy is increased during in vitro decidualization of human endometrial stromal cells. Furthermore, we demonstrate that the knockdowns of two important autophagy-related (ATG) proteins, ATG7 and ATG5, impaired decidualization, confirming a positive role of these proteins and of autophagy for the correct decidualization of human endometrial stromal cells. In conclusion, in this work, we describe a previously unknown functional connection between autophagy and endometrial physiology.
| S-EPMC6628477 | biostudies-literature
Project description: Not available
| S-EPMC4871191 | biostudies-literature
Project description:Decidualization of the endometrial stromal cells (ESCs) is essential for successful embryo implantation. It involves the transformation of fibroblastic cells into epithelial-like cells that secrete cytokines, growth factors, and proteins necessary for implantation. Previous studies have revealed altered expression of miR-375 in the endometrium of patients with recurrent implantation failure and the ectopic stromal cells of patients with endometriosis. However, the exact molecular mechanisms, particularly the role of microRNAs (miRNAs) in the regulation of decidualization, remain elusive. In this study, we investigated whether decidualization is affected by miR-375 and its potential target(s). The findings demonstrated the downregulation of the expression of miR-375 in the secretory phase compared to its expression in the proliferative phase of the endometrium in normal donors. In contrast, it was upregulated in the secretory phase of the endometrium in infertility patients. Furthermore, during decidualization of ESCs in vitro, overexpression of miR-375 significantly reduced the transcript-level expression of forkhead box protein O1 (FOXO1), prolactin (PRL), and insulin-like growth factor binding protein-1 (IGFBP1), the well-known decidual cell markers. Overexpression of miR-375 also resulted in reduced decidualization-derived intracellular and mitochondrial reactive oxygen species (ROS) levels. Using the luciferase assay, we confirmed that NADPH oxidase 4 (NOX4) is a direct target of miR-375. Collectively, the study showed that the miR-375-mediated NOX4 downregulation reduced ROS production and attenuated the decidualization of ESCs. It provides evidence that miR-375 is a negative regulator of decidualization and could serve as a potential target for combating infertility.
| S-EPMC9646565 | biostudies-literature
Project description:BackgroundThe precise pathogenesis of poor endometrial receptivity in recurrent implantation failure (RIF) remains unclear. This study was aimed at exploring the effects of different CD44 isoforms in the mid-secretory phase endometrium on endometrial receptivity in women with RIF.MethodsMid-secretory phase endometrial tissue samples were obtained from the following two groups of women who had undergone IVF: (a) 24 patients with RIF and (b) 18 patients with infertility due to tubal obstruction, who had achieved a successful clinical pregnancy after the first embryo transfer in IVF (control group). Identification of differentially expressed CD44 isoforms in endometrial tissues was assessed using immunohistochemistry, qPCR, and western blotting. Effects of overexpression and knockdown of CD44v3 on proliferation and decidualization of immortalized human endometrial stromal cells (T-HESCs) and primary HESCs were investigated by qPCR and western blot analysis. A heterologous coculture system of embryo implantation was constructed to mimic the process of trophoblast invasion during implantation.ResultsThe expression of CD44v3 was significantly higher in the mid-secretory phase of endometrial stromal cells than in the proliferation phase, but was notably lower in RIF patients. Knockdown of CD44v3 significantly downregulated cell proliferation both in T-HESCs and HESCs. The expression of decidualization markers, prolactin (PRL) and insulin like growth factor binding protein-1 (IGFBP1), was notably decreased following the knockdown of CD44v3, whereas the expression of both PRL and IGFBP1 increased after its overexpression in HESCs. Furthermore, the CD44v3-knockdown HESCs displayed significant deficiency in supporting trophoblast outgrowth in a coculture system of embryo implantation; however, overexpression of CD44v3 in HESCs promoted trophoblast outgrowth.ConclusionThe reduced expression of CD44v3 suppresses the proliferation and decidualization of HESCs, which might play a pivotal role in poor endometrial receptivity in women with RIF.
| S-EPMC9756673 | biostudies-literature
Project description:BackgroundPoor decidualization and abnormal autophagy conditions in the endometria of adenomyosis patients have been reported previously. However, the specific regulatory mechanism of decidualization in adenomyosis and its relationship with autophagy levels have not been clarified.MethodsEndometrial tissues from adenomyosis patients and uteri from an adenomyosis mouse model were collected for the detection of different expression patterns of KLF4 and autophagy markers (LC3-B/LC3-A and Beclin-1) compared with control groups. Human endometrial stromal cells (hESCs) isolated from adenomyosis and control endometrial tissues were employed to elucidate the biological functions of KLF4 in autophagy and decidualization. Gene expression regulation was examined by quantitative real-time PCR (qRT-PCR), western blotting and luciferase reporter assays. In addition, DNA promoter-protein interactions were examined by chromatin immunoprecipitation (ChIP)/PCR assay and avidin-biotin conjugate DNA precipitation (ABCD) assay.ResultsKLF4 expression was decreased in endometrial tissues from adenomyosis patients compared with those from fertile controls, especially in stromal compartments. The opposite results were observed for autophagy marker (LC3-B/LC3-A and Beclin-1) expression. At the same time, KLF4 reversed the poor decidualization of hESCs from adenomyosis patients. In addition, KLF4 could induce hESC decidualization by promoting the autophagy level. Mechanistically, KLF4 bound to a conserved site in the autophagy-related 5 (ATG5) promoter region and promoted ATG5 expression. Similar expression patterns of KLF4 and autophagy markers were detected in adenomyotic mice.ConclusionsKLF4 overexpression increases the autophagy level of hESCs by transcriptionally promoting ATG5 expression, and abnormally decreased KLF4 in adenomyosis impairs hESC decidualization by repressing autophagy.
| S-EPMC9238063 | biostudies-literature
Project description:Nucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization.Endometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 μM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system.NLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over-expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity.NLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells.
| S-EPMC5558772 | biostudies-other
Project description:Infertility and early embryo miscarriage is linked to inadequate endometrial decidualization. Although transcriptional reprogramming is known to drive decidualization in response to progesterone, the key signaling effectors that directly mediate this hormone response are not fully known. This knowledge gap is clinically significant because identifying the early signals that directly mediate progesterone-driven decidualization will address some of the current limitations in diagnosing and therapeutically treating patients at most risk for early pregnancy loss. We recently revealed that the promyelocytic leukemia zinc finger (PLZF) is a direct target of the progesterone receptor and is essential for decidualization of human endometrial stromal cells (hESCs). The purpose of this current work was to identify the genome-wide transcriptional program that is controlled by PLZF during hESC decidualization using an established in vitro hESC culture model, siRNA-mediated knockdown methods, and RNA-sequencing technology followed by bioinformatic analysis and validation. We discovered that PLZF is critical in the regulation of genes that are involved in cellular processes that are essential for the archetypal morphological and functional changes that occur when hESCs transform into epithelioid decidual cells such as proliferation and cell motility. We predict that the transcriptome datasets identified in this study will not only contribute to a broader understanding of PLZF-dependent endometrial decidualization at the molecular level but may advance the development of more effective molecular diagnostics and therapeutics for the clinical management of female infertility and subfertility that is based on a dysfunctional endometrium.
| S-EPMC5819842 | biostudies-other
Project description:Vaginal bleeding and subchorionic hematomas are associated with increased risk of both early and late pregnancy loss. Thrombin generation may play a pivotal role in the development of these complications. To determine the effects of thrombin on human endometrial stromal cells (hESCs), cells were treated with thrombin at baseline or during decidualization with cyclic adenosine monophosphate (cAMP)+medroxyprogesterone acetate (MPA). Next-generation RNA sequencing revealed that markers of decidualization (IGF-1, IGFBP-1, and prolactin [PRL]) were induced after the initiation of decidualization, whereas thrombin suppressed insulin-like growth factor ( IGF)-1, Insulin-like growth factor binding protein ( IGFBP)-1, and PRL gene expression at baseline and during decidualization. These effects were mediated through protease activated receptor (PAR)-1- and PAR-1-independent pathways. Thrombin decreased the secretion of a key marker of decidualization (PRL), altered the morphological transformation of decidualizing hESCs, and activated genes involved in matrix degradation and proinflammatory chemokines ( Interleukin-8 and Interleukin-6). Genes encoding factors important for matrix stability ( Col1α1, LOX) were suppressed. We suggest that intrauterine bleeding and generation of thrombin accentuates leukocyte extravasation and endometrial inflammation, impairs decidualization, and endometrial support of early pregnancy.
| S-EPMC6728565 | biostudies-literature
Project description:This study examined the effect of bisphenol A (BPA) exposure on human uterine stromal fibroblast cells (HuF) undergoing decidualization. HuF cells were isolated and cultured for eight days in the presence of a decidualization-inducing cocktail, while concurrently exposed to physiological and supra-physiologic doses of BPA (1ng/mL, 10ng/mL, 0.5?g/mL, 10?g/mL and 20?g/mL). Decidualization markers, steroid hormone receptors and cell cycle gene expression were detected by qRT-PCR and cellular proliferation was assessed by KI-67 immunofluorescent staining and MTS assay. BPA impaired decidualization at 10?g/mL and 20?g/mL, but not at lower doses. Additionally, BPA at 20?g/mL decreased progesterone receptor and estrogen receptor-alpha compared to controls. The highest dose of BPA also reduced cellular proliferation and cyclin D2 expression compared to controls. These findings demonstrate that BPA disrupts in vitro decidualization of uterine stromal fibroblasts by altering steroid hormone receptor expression at higher concentrations but not at lower physiological doses.
| S-EPMC5892434 | biostudies-literature
Project description:Human endometrium decidualization, which involves endometrial stromal proliferation and differentiation, is a prerequisite for embryo implantation, thus successful pregnancy. The Forkhead Box M1 (FoxM1), previously known as HNF-3, HFH-11, MPP2, Win, and Trident, is a transcriptional factor that plays crucial roles in cell proliferation and cell cycle progression. However, the molecular mechanism of FoxM1 during human endometrial decidualization remains unexplored. In this study, we first found FoxM1 is dynamically expressed in human endometrium during menstrual cycle. Employing a human endometrial stromal cell (HESC) line, we then demonstrated that FoxM1 inhibition downregulates cyclin B1 expression, delaying G2/M phase transition during HESC proliferation. Additionally, loss of FoxM1 expression blocks the differentiation of HESCs in response to estrogen, progesterone, and dbcAMP. Applying chromatin immunoprecipitation (ChIP) technique and luciferase assay, we further approved that FoxM1 can transcriptionally active signal transducer and activator of transcription 3 (STAT3), ensuring normal HESC differentiation. Besides enriching our knowledge on molecular basis underlying stromal decidualization, these findings help to shed light on the potential molecular causes for the endometrial disorders in humans.
| S-EPMC4558550 | biostudies-literature