Increased AIF-1-mediated p38 MAPK Phosphorylation in the Mid-secretory Endometrium Impairs Endometrial Receptivity in Women with Recurrent Implantation Failure
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE297873 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Recurrent implantation failure (RIF) presents a significant challenge in the field of assisted reproductive technology, primarily stemming from compromised decidualization that impacts endometrial receptivity. Despite ongoing research efforts, the comprehensive molecular regulatory mechanisms involved in RIF remain incompletely understood. This study revealed significantly reduced levels of secretoglobin, family 2A, member 1 (SCGB2A1) in both the mid-secretory endometrium and uterine fluid of RIF patients compared to control subjects. Besides, combined with RNA sequencing results, we demonstrated that the suppression of SCGB2A1 results in reduced cell proliferation and impaired decidualization by modulating CDK3 signaling during cell cycle transition in immortalized human endometrial stromal cells (T-HESCs) and primary HESCs. Furthermore, our findings indicated that inhibition of endometrial SCGB2A1 in a rat model hinders embryo implantation and disrupts decidualization. In conclusion, this study provides evidence that SCGB2A1 serves as a novel biomarker for endometrial receptivity and plays a crucial role in the regulation of human endometrial decidualization. The findings offer valuable insights into the pathogenesis of decidualization-related RIF and have the potential to enhance strategies for improving pregnancy outcomes.
2025-01-01 | GSE269408 | GEO
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:Study question : Are there changes in transcript levels as endometrial receptivity changes in patients with recurrent implantation failure (RIF), particularly in alternative splicing events (ASEs), differential expression genes (DEGs) and immune cells levels? Summary answer: Changes in endometrial receptivity affect alternative splicing (AS), differential gene expression and immune cells, and the RNA-binding protein (RBP) KHDRBS3 likelymaybe？ Likely？ is involved in the dysregulation of alternative splicing. What is known already: Endometrial receptivity is critical for RIF patients. Researchers have developed transcript level-based models to predict personalized endometrial assessment at WOI. Investigating alternative splicing dysregulation, immune cells and other transcriptional biomarkers in RIF patients may further help to predict endometrial receptivity and improve embryo implantation success. Study design, size, duration: 90 endometrial samples were collected from fertile healthy controls (HC) during the menstrual cycle, including pre-receptive (PR) (luteinising hormone (LH)+3 days/LH+5 days), receptive (R) (LH+7 days) and post-receptive (PS) (LH+9 days) phases. 73 endometrial samples were taken from RIF patients on hormone replacement therapy (HRT) cycles, including PR (progesterone (P)+3 days), R (P+5 days) and PS (P+7 days) phases. Participants/materials, setting, methods: Total RNA was extracted and sequenced for all 163 endometrial samples . Bioinformatic analysis was used to comprehensively investigate the endometrial transcriptome at different stages of receptivity. We elucidated the biological significance of the universal alteration of alternative splicing in endometrial receptivity and further analyzed the role of immune cells and gene expression in this process. In addition, an ASEs-RBPs correlation network was constructed in the endometrial receptive period to evaluate the dysregulation of AS by RBPs. Main results and the role of chance: Global splicing profiling of the four subgroups (HC: PR vs. R; HC: PS vs. R; RIF: PR vs. R; RIF: PS vs. R) consistently showed that skipped exons (SE) and mutually exclusive exons (MXE) were the most common changes in splicing events. These different ASEs occurred at high frequency and some of them could affect the coding potential of a transcript. A greater number of genes with different alternative splicing events (ASEGs) were identified between PR and R phases than between PS and R phases, and the same trend was observed for differentially expressed genes (DEGs). Both ASEGs and DEGs showed enrichment for pathways associated with cell function and adhesion, while DEGs were also enriched for cytokine and immune-related pathways. Immune cell prediction shows that changes in endometrial receptivity phases result in differences in the levels of CD8 T cells, resting NK cells and other immune cells. During the R phase, there was a significant decrease in CD8 T cells and resting NK cells, whereas monocytes and M0 macrophages were significantly increased compared to the endometrial PR phase in RIF patients. Similarly, analysis of immune cells showed a significant increase in CD8 T cells, M1 and M2 macrophages and a significant decrease in activated NK cells in the R phase compared to the PS phase of the endometrium in RIF patients. Some of these immune cells, such as NK cells and monocytes, are highly correlated with certain ASEs. Investigation of ASEs-RBPs networks suggested that KHDRBS3 may be a key regulator of splicing events. Limitations, reasons for caution: The sample size needs to be increased and cover a variety of situations, such as different age, pathology, dietary habits, etc., and alsothe molecular experimental validation needs to be considered. The lack of direct comparisons between natural and HRT cycles in the same sample and molecular experimental validation need to be considered. Wider implications of the findings: Comprehensive transcriptional analysis of the endometrium provide valuable insight into potential biomarkers related to endometrial receptivity and potential treatments for RIF patients. Study funding/competing interest(s): This study was supported by Supported by the Program of National Natural Science of China (Grant No. 81701409). All authors declared that they have no conflicts of interest.
2025-10-15 | GSE287072 | GEO
Project description:This study delineates the immune and transcriptional landscape of endometrial receptivity at the P5 phase via triad analysis of Endometrial Intraepithelial Neoplasia/Early Endometrial Cancer (EIN/ECa, N = 64), Repeated Implantation Failure (RIF, N = 25), and control (Ctrl., N = 3)) endometrial profiles. RNA sequencing and deconvolution algorithms identified differential gene expression, immune cell composition, and pathway enrichments. EIN/ECa exhibited dysregulated complement/coagulation cascades and proliferation-related genes, suggesting a pro-proliferative/inflammatory microenvironment. RIF showed immune pathway perturbations, with abnormal TLR4 and CXCL10 expression disrupting maternal-fetal tolerance. Integrative analysis revealed distinct molecular signatures: EIN/ECa prioritized oncogenic proliferation, while RIF focused on immune tolerance defects.These findings illuminate phase-specific endometrial receptivity mechanisms, providing targets for improving fertility outcomes in high-risk groups.
2025-08-25 | GSE305811 | 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:Study question: Does a comprehensive study involving two different population cohorts and small RNA sequencing from endometrium and blood reveal new endometrial receptivity-related microRNAs (miRNAs) in healthy conditions and in women with recurrent implantation failure (RIF)? Summary answer: Several annotated miRNAs, not previously associated with endometrial receptivity, as well as one novel miRNA were found as differentially expressed between early secretory vs. mid-secretory phase samples in addition to miRNAs dysregulated in RIF patients. What is known already: The involvement of miRNAs in mid-secretory endometrial functions has been shown and aberrant expression of miRNAs in RIF has been identified in a few previous studies, but not from whole blood samples. However, as the analysis settings and platforms have been different and a small number of samples has been analysed, there is no consensus about the miRNAs involved in endometrial receptivity and dysfunction. Participants/materials, setting, methods: A total of 116 endometrial and 114 blood samples were subjected to Illumina small RNA sequencing. Identification of annotated and novel miRNAs from sequencing reads was performed by miRDeep2 algorithm. miRNAs that had significantly altered levels between the study groups in both EST and ESP datasets were considered as differentially expressed. Ingenuity Pathway Analysis was applied for identifying miRNA target genes and respective canonical pathways from the matched mRNA analysis from the same samples. Custom TaqMan Small RNA assay was used for the validation of novel miRNA (chr2_4401) levels from paired early secretory and mid-secretory endometrial samples. Main results and the role of chance: Among fertile women, 91 differentially expressed miRNAs were identified in mid-secretory vs. early secretory endometrium, while no differentially expressed miRNAs were found in the corresponding blood samples. The comparison of mid-secretory phase samples between fertile women and RIF patients revealed 21 differentially expressed miRNAs from endometrium and one from blood samples. miRNA target gene prediction analysis using our mRNA sequencing data from the matched samples detected several canonical pathways to be involved in mid-secretory endometrial functions, including JAK/STAT signalling, leptin signalling and growth hormone signalling. Moreover, JAK/STAT signalling pathway was also revealed in miRNA target analysis of mid-secretory endometrium from RIF patients when compared to fertile women. Further, our study results highlight the involvement of miR-30 and miR-200 families in endometrial receptivity, and miR-424-5p in the development of endometrial dysfunction. We identified several novel miRNAs, of which miRNA chr2_4401, being 37-fold up-regulated in mid-secretory phase, has a potential role in the mid-secretory endometrial functions. From blood samples we identified miR-30a-5p as a possible marker of infertility related to RIF.
2019-07-18 | GSE108966 | GEO
Project description:Understanding human endometrial dynamics remains a challenge, limiting early diagnosis and treatment of reproductive disorders. Here, we decoded the normal endometrial dynamics across the window of implantation (WOI) and its deficiency in endometrium from women with recurrent implantation failure (RIF) by analyzing data from over 220,000 cells, together with developing a computational model StemVAE that is capable of both temporal prediction and pattern discovery. Our time-series atlas highlighted a two-stage stromal decidualization process whereas a gradual epithelial transitional process across the WOI allowing the identification of a time-varying gene set regulating epithelial receptivity. The epithelial receptivity genes were able to stratify the RIF endometrium into two classes of receptivity-deficiency involving early and late implantation. Further investigation uncovered epithelial cell dysfunction under hyperinflammatory microenvironment in RIF endometrium. The holistic characterization of physiological and pathophysiological WOI, and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments.
2024-11-18 | GSE250130 | GEO
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.
2022-09-16 | GSE183837 | GEO
Project description:The objectives of the present study were to determine whether obesity impacts human decidualization and the endometrial control of trophoblast invasion (both of which are required for embryo implantation) and evaluate the potential involvement of endometrial extracellular vesicles (EVs) in the regulation of these physiological processes. Using primary human cell cultures, we first demonstrated that obesity is associated with significantly lower in vitro decidualization of endometrial stromal cells (ESCs). We then showed that the trophoblastic cell line’s invasive ability was greater in the presence of conditioned media from cultures of ESCs from obese women. Using mass-spectrometry-based quantitative proteomics, we found that EVs isolated from uterine supernatants of biopsies from obese women (vs. nonobese women) presented a molecular signature focused on cell remodeling and angiogenesis. Lastly, the results of functional assays indicated that supplementation of the culture medium with EVs from nonobese women can rescue (at least in part) the defect in in vitro decidualization described in ESCs from obese women. Lastly, the addition of endometrial EVs from obese women (vs. nonobese women) was associated with significantly greater invasive activity by HTR-8/SVneo cells. In conclusion, our results provided new insights into the endometrial EVs’ pivotal role in the poor uterine receptivity observed in obese women.
2023-10-09 | PXD039568 | Pride
Project description:Proper decidualization is vital in preparation for a potential embryo receptivity, placentation, menstrual health and subsequent endometrial regeneration. Given the importance of extracellular vesicles (EVs) in intercellular communication, and recently in embryo implantation and indicators of menstrual cycle and fertility, we investigated their role during decidualization. Overall, this study provides an insight into distinct variation in sEV composition depending upon the level of decidualization of endometrial stromal cells, with the signaling potential to coordinate endometrial health ranging from embryo implantation, facilitating placentation and subsequent endometrial regeneration.
2021-11-17 | PXD026342 | Pride