Immune and Transcriptional Landscape of Endometrial Receptivity at P+5 Phase: A Triad Analysis of EIN, RIF, and Control Endometrial Profiles
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE305811 | GEO | 2025/08/25
REPOSITORIES: GEO
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Project description:Impaired endometrial receptivity is one of the major causes of recurrent implantation failure (RIF), and the underlying molecular mechanism has not been fully elucidated. We demonstrated that Chromodomain Y like (CDYL) was highly expressed in the endometrium at mid-secretory phase during the normal menstrual cycles. However, the expression of CDYL was down-regulated in the endometrial tissues obtained from women with RIF, consistently with the protein level of LIF, which is the marker of endometrial receptivity. Knockdown of CDYL significantly decreased the cell migration of human endometrial Ishikawa cells and primary endometrial cells. Genomic analyses revealed that CDYL gene silencing resulted in decreased expression of many genes associated with cytoskeleton and migration regulation.
2020-09-28 | GSE141239 | GEO
Project description:Endometrial receptivity is imperative to achieving pregnancy in humans. A disruption in the development of endometrial receptivity is responsible for recurrent implantation failures (RIF) of endometrial origin. To further understand the molecular mechanisms behind the endometrial receptivity process, we used the 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) method to compare and quantify the proteomes from endometrial biopsies of three different endometrial statuses (fertile women, IUD carriers and RIF patients). Overall, iTRAQ allowed to identify 1,889 non-redundant proteins. Of these, 188 were differentially expressed proteins (DEP) (p-value < 0.05) among the three endometrial groups. Pairwise comparisons revealed 133 significant DEP in fertile vs. IUD carriers and 158 DEP in RIF vs. IUD carriers. However, no DEP were identified between fertile and RIF patients. Western blot validation of three DEP involved in endometrial receptivity (Plastin 2, Lactotrasferrin, and Lysozyme) confirmed our iTRAQ results. Moreover, functional KEGG enrichment revealed that complement and coagulation cascades and peroxisome were the two most significant pathways for the RIF vs. IUD comparison and ribosome and spliceosome for the fertile vs. IUD comparison, as possible important pathways involved in the endometrial receptivity acquisition. Our findings confirm that an IUD introduces numerous changes in the endometrial protein profile when compared to fertile and RIF endometria, revealing some key proteins involved in endometrial receptivity. The lack of DEP between fertile and RIF patient endometria suggest either that idiopathic RIF may not have an endometrial origin, with other as-yet-unknown factors involved.
2019-11-06 | PXD011094 | Pride
Project description:The molecular mechanisms underlying window of implantation (WOI) displacement in patients with recurrent implantation failure (RIF) remain unclear. This study aims to explore the transcriptomic signatures of endometrium with normal and displaced WOIs during HRT cycles and to identify the causes of endometrial receptivity (ER) abnormalities and WOI displacement in RIF patients. 40 RIF patients were recruited and underwent personalized embryo transfer (pET) guided by the predicted results of endometrial receptivity diagnosis (ERD) model. Transcriptome analysis of endometrium from patients with clinical pregnancies after pET was performed to identify differentially expressed genes (DEGs) associated with WOI displacement. The ERD results indicated that 67.5% of RIF patients (27/40) were non-receptive in the conventional WOI (P+5) of the HRT cycle. The clinical pregnancy rate in RIF patients improved to 65% (26/40) after ERD-guided pET, indicating the effectiveness of transcriptome-based WOI prediction. Among the 26 patients with clinical pregnancy, the gene expression profiles of P+5 endometrium from advanced (n=6), normal (n=10) and delayed (n=10) WOI groups were significantly different from each other. 10 DEGs (CES4A, LRRC1, SLC25A48, TM4SF4, DPP4, CXCR1, CXCR2, OSM, LCN2 and TNFRSF10C ) identified among P+5 endometrium of 3 groups were involved in immunomodulation, transmembrane transport and tissue regeneration, which could accurately classify the endometrium with different WOIs.
2024-01-03 | GSE252280 | GEO
Project description:Endometrial receptivity (ER) refers to the ability of the endometrium to accept embryos in the window of implantation during which the endometrial tissue allows embryo implantation and pregnancy initiation. In women with certain gynecological diseases, including polycystic ovary syndrome, tubal disease and endometriosis, ER appears to be impaired, leading to infertility and pregnancy failure. Ligustilide (LIG) treatment can restore endometrial receptivity and promote implantation in pregnant rats with low endometrial receptivity (LER). However, the mechanism by which LIG affects LER is unknown. In the current study,we conducted a bioinformatic analysis of endometrial tissues of rats with NER, LER, and LIG-treated LER.
2025-07-03 | GSE301071 | GEO
Project description:Summary Answer: HPL treatment stimulates endometrial growth and trophoblast attachment by activating cell proliferation, and modulating cell-cell signaling and extracellular matrix organization. What is known already: Despite advancements in RIF management, there is currently no standard therapy, and existing treatments have variable effectiveness and do not consistently improve clinical pregnancy rates. There is a general consensus that intrauterine infusion of aPRP, before embryo transfer, promotes endometrial growth and may be the most effective immunomodulatory intervention to significantly improving pregnancy outcomes in RIF patients. Study design, size, duration: Cross-sectional (control versus treatment) study including five non-RIF (control) patients and eighteen RIF patients from the CReATe Fertility Centre, Toronto. The eighteen RIF patients were categorized into two sub-groups: RIF and RIF+TE. Participants/materials, setting, methods: Endometrial tissue was collected from pre-menopausal women (32-47 years of age) during routine biopsy procedures at the CReATe Fertility Centre, Toronto. Primary endometrial epithelial (EECs) and stromal cells (ESCs) were enzymatically isolated, cultured separately, and treated for 48 hours with either SFM (SFM) as the untreated control, or SFM supplemented with 1% HPL (EECs), or 10% HPL (ESCs). Cell proliferation was assessed using the PrestoBlueTM reagent (metabolic assay) and immunocytochemistry for Ki-67 expression. Following 48-hour treatment, total RNA was isolated from untreated and treated cells to prepare pooled RNA libraries, which were then subjected to RNA sequencing (150 cycles paired-end). Differential gene expression was performed using the DESeq2 package and RStudio/R. Significant differentially expressed genes were determined with the following cut off values: log2FoldChange >|2| and padj <0.05. Pathway enrichment analysis was then performed with Enrichr (Reactome 2022 database) to identify enriched pathways. After 48-hour treatment with SFM or HPL, a trophoblast attachment assay was also performed with fluorescently labeled HTR-8/SVneo trophoblast spheroids, where spheroids were seeded on top of pre-treated EEC monolayers for a 1-hour incubation to allow for attachment. Fluorescent microscopy and ImageJ™ software were used to image and quantify the total number of seeded and attached spheroids. Main results and the role of chance: Treatment with non-autologous HPL for 48 hours significantly increased EEC proliferation by 1.24- to 1.49-fold (P<.05) in all groups. ESCs showed a significant proliferation increase of 1.29-fold in the proliferative phase RIF group and 1.92-fold in the secretory phase RIF+TE group (P<.05). HPL treatment upregulated 45 genes in EECs, including MMP1, MMP9, and ADAMTS18, while 378 genes were upregulated in ESCs, such as BUB1, CDK1, MKI67, and PLK1. Twenty-two common genes were significantly upregulated in both cell types. EECs had 30 downregulated genes, including KL and ADRA2A, while ESCs had 429 downregulated genes, such as PTGIS, PTGDS, and PTGES, with seven common genes downregulated in both cell types. Pathway enrichment analysis revealed that upregulated pathways in EECs included extracellular matrix organization and degradation, while ESCs showed enrichment in cell cycle (mitotic), cell cycle checkpoints, and extracellular matrix degradation. Downregulated pathways included receptor signaling of the fibroblast growth factor receptor 1 in EECs, prostaglandin synthesis in ESCs, and G-protein coupled receptor signaling in both cell types. HPL treatment also increased primary EEC attachment to trophoblast spheroids compared to the untreated control. This increased attachment was consistent in EECs from RIF patients, regardless of endometrial thickness, with a 26% increase (from 42.58% to 68.90%, P<.01) in RIF cultures and a significant 29% increase (from 57.52% to 86.5%, P<.01) in RIF+TE cultures. Limitations, reasons for caution: One limitation is the small sample size of primary human endometrial samples (N=23), divided into four patient groups (N=5-6 per group). Additionally, all participants were pre-menopausal women aged 32-47, most of whom fall into the advanced reproductive age category (>35 years), a group often recommended for infertility assessment after six months of unsuccessful conception attempts. Although our study utilized primary endometrial cells and indicates that HPL may be an effective treatment for RIF and TE, these in vitro findings need to be validated in vivo. Clinical studies, such as randomized controlled trials, are necessary to evaluate and compare the efficacy of commercial HPL as a treatment alternative to aPRP. These trials would also allow for testing the safety of using a commercial non-autologous HPL product in human patients and help optimize treatment protocols, including the ideal dosage, concentration, timing, and treatment duration to maximize therapeutic benefits and develop more effective treatments for patients with endometrial causes of RIF. Wider implications of the findings: Platelet-rich plasma (PRP) treatment for RIF and TE is increasingly being adopted by fertility clinics worldwide. Our research represents the first detailed investigation into the molecular effects of HPL, a derivative of PRP, on primary endometrial cells from patients with RIF, establishing a foundation for understanding how PRP/HPL impacts endometrial growth and receptivity. Our study demonstrated that commercial non-autologous HPL stimulates endometrial cell proliferation, modulates the expression of factors related to cell mitosis, extracellular matrix remodeling, and cell-cell signaling, and enhances endometrial-embryo attachment. By elucidating the mechanistic actions of HPL, our research provides valuable insights into this therapeutic approach and informs future treatments aimed at improving embryo transfer success. While these findings suggest that HPL could be as effective as aPRP, further investigation is necessary to evaluate its safety and efficacy in humans, necessitating comprehensive studies before HPL can be routinely used in clinical practice. Study funding/competing interest(s): This study was funded by the CReATe Fertility Centre.
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2022-06-09 | PXD024735 | Pride
Project description:Despite great advances in assisted reproductive technology (ART), unexplained recurrent implantation failure (RIF) due to disorder of endometrial receptivity still cannot be effectively avoided. More importantly, cell characteristics and cell communication that regulate endometrial receptivity and differentiation, and its disorders in RIF at the window of implantation (WOI) remain rudimentary. Here we characterized the transcriptomes of four major cells in human endometrium from healthy control and RIF patients at single-cell resolution. We discovered the dynamic change characteristics of four major endometrial fibroblast-like cells with different endometrial receptivity, reported a novel pluripotent endometrial glandular epithelial cell with high levels of progesterone receptor and exosomes, and defined a unique ITGA1+CXCR4+ NK cell for connecting endometrial nonimmune cells and immune cell infiltration at the WOI. Additionally, we developed a systematic repository of cell-cell communication for endometrial differentiation and the opening of endometrial receptivity via the ligand-receptor complexes interactions. Our study provides deeper insights into aberrant molecular and cellular characterizations, and the endometrial microenvironmental disorders of RIF patients that are potentially applicable to improve the etiological diagnosis and therapeutics of unexplained RIF.
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