Deficiency of Sirtuin 1 Impedes Endometrial Decidualization in Recurrent Implantation Failure Patients

Decidualization is driven by differentiation of human endometrial stromal cells (ESCs), and is a prerequisite for successful implantation and establishment of pregnancy. The critical role of impaired decidualization in women suffered recurrent implantation failure (RIF) has been established, while the underlying mechanism is poorly understood. In the present study, we verified the essential role of Sirtuin1 (SIRT1) in regulating differentiation and maintaining reactive oxygen species (ROS) homeostasis of human ESCs during decidualization. The abundance of SIRT1 was decreased in RIF patients both in the endometria during window of implantation phase and in the decidualized ESCs. Downregulation of SIRT1 disrupted the intracellular ROS homeostasis during decidualization of ESC, manifested as the accumulation of intracellular ROS level and the reduction of antioxidant stress molecules. Elimination of ROS with N-acetyl-L-cysteine (NAC) could rescued the decidualization inhibition caused by SIRT1 knockdown. Further, we explored the insufficient expression of SIRT1 in ESC affected the deacetylation of forkhead box O1 (FOXO1), and thus inhibited the transcriptional activity of FOXO1. This could account for the dysregulation of intracellular ROS homeostasis during decidualization and decreased expression of decidual markers. Collectively, our findings provided insight into the role of down-regulated SIRT1 in the poor decidual response of ESCs in RIF patients.

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Increased expression of HMGB1 in the implantation phase endometrium is related to recurrent implantation failure

10.21203/rs.3.rs-695265/v1 ◽

2021 ◽

Author(s):

Mi Han ◽

Yi Cao ◽

Wenjie Zhou ◽

Mingjuan Zhou ◽

Xiaowei Zhou ◽

...

Keyword(s):

Epithelial Cells ◽

Underlying Mechanism ◽

Endometrial Receptivity ◽

In Vitro Assays ◽

Control Group ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Tubal Infertility ◽

Endometrial Stromal Cells

Abstract Impaired endometrial receptivity is the main cause of recurrent implantation failure (RIF), however, its underlying mechanism is unclear. In this study, we found that HMGB1 expression was significantly decreased in the implantation phase endometrium in the control group (patients with tubal infertility who successfully achieved conception after the first embryo transfer) (P = 0.006). However, the expression levels of HMGB1 mRNA and protein were significantly upregulated during the implantation phase in endometrial tissues obtained from patients with RIF compared to those in the control group (P = 0.001), consistent with the results of genome-wide expression profiling. Moreover, in vitro assays showed that increased expression of HMGB1 in human endometrial epithelial cells cause marked deficiency in supporting blastocysts and human embryonic JAR cell adhesion, mimicking the process of embryo adhesion. However, overexpression of HMGB1 had no effect on cell proliferation and in-vitro decidualization in a human endometrial stromal cell line (T-HESCs) and in primary human endometrial stromal cells (HESCs). These findings indicate that increased HMGB1 levels suppressed the adhesion capability of epithelial cells, contributing to impaired endometrial receptivity in patients with recurrent implantation failure. This characteristic can be used as a target for detecting and treating recurrent implantation failure in clinical practice.

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Identification of a lncRNA-Related Competing Endogenous RNA Network in Recurrent Implantation Failure

10.21203/rs.3.rs-1013014/v2 ◽

2021 ◽

Author(s):

Kai Huang ◽

Ying Shi ◽

Gezi Chen

Keyword(s):

Underlying Mechanism ◽

Control Group ◽

Implantation Failure ◽

Rna Seq ◽

Recurrent Implantation Failure ◽

Cerna Network ◽

Regulation Network ◽

Competing Endogenous Rnas ◽

Competing Endogenous Rna Network

Abstract Background Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.

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Identification of a lncRNA-related Competing Endogenous RNA Network in Recurrent Implantation Failure

10.21203/rs.3.rs-1013014/v1 ◽

2021 ◽

Author(s):

Kai Huang ◽

Ying Shi ◽

Gezi Chen

Keyword(s):

Underlying Mechanism ◽

Control Group ◽

Implantation Failure ◽

Rna Seq ◽

Recurrent Implantation Failure ◽

Cerna Network ◽

Regulation Network ◽

Competing Endogenous Rnas ◽

Competing Endogenous Rna Network

Abstract Background: Impaired endometrial receptivity is supposed to be a major element leading to recurrent implantation failure (RIF). Numerous studies have identified that the lncRNAs-miRNAs-mRNAs regulation network functions in the generation of receptive uterus. Long non-coding RNAs could act as competing endogenous RNAs in the pathogenesis of RIF. However, our understanding of the underlying mechanism is still limited. Results: Based on the RNA-Seq results, 617 DEmRNAs, 69 DElncRNAs and 107 DEmiRNAs were identified in the RIF group compared with the control group. To investigate the role of lncRNAs in RIF, we constructed a lncRNA related ceRNA network. A total of 3 lncRNAs, 8 miRNAs and 69 genes were identified. Above all, our study obtained 120 lncRNAs-miRNAs-mRNAs relationships in the ceRNA network. Among three hub lncRNAs, PART1 and PWRN1 were upregulated whereas PGM5P3-AS1 was downregulated in RIF endometrium. Meanwhile, three down-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-134-5p, hsa-miR-1225-5p) and five up-regulated miRNAs (hsa-miR-30c-5p, hsa-miR-30b-5p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-196b-5p) were shown. Conclusions: We constructed a lncRNA-related ceRNA network and identified three hub lncRNAs in recurrent implantation failure. The results may provide further understanding in the pathogenesis of RIF as well as potential diagnostic and therapeutic targets.

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Role of T cells in intrauterine administration of activated peripheral blood mononuclear cells in recurrent implantation failure.

10.1101/2021.01.06.425452 ◽

2021 ◽

Author(s):

Guillaume Ricaud ◽

Cathy Vaillancourt ◽

Veronique Blais ◽

Marjorie Disdier ◽

Fabien Joao ◽

...

Keyword(s):

T Cells ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Treg Cells ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

Intrauterine administration of autologous peripheral blood mononuclear cells (PBMC) has been recently proposed as new immunotherapy for patients with unexplained recurrent implantation failure (RIF). In these patients, administration of activated PBMC 24-h or 72-h before embryo transfer resulted in a 3-fold increase in biochemical pregnancy rate. In this study we evaluated the role of T cells to promotes human endometrial receptivity. On the day of ovulation, PBMC were isolated from and activated with T cells mitogen, the phytohemagglutinin (PHA) and hCG for 48-h in a conditioned culture medium. Distributions of CD4+ T cells were characterized in 157 patients by flow cytometry before and after PHA/hCG activation. Cytokine production was analyzed by cytometric beads array. We observed in RIF patients a significant decrease in Th2 and natural Treg cells before activation with PHA/hCG and an increase of Th17 cells after activation compared to intrauterine sperm insemination (IUI) and in vitro fertilization (IVF) groups. Furthermore, the hCG/PHA treatment increases anti-inflammatory T cells (Th2 and Treg cells) compared to non-treated T cells. Principal component analysis (PCA) performed on CD4 T cell subtypes revealed a different cellular profile in the RIF compared to the IUI and IVF groups. This inflammatory state change could explain how endometrium immunomodulation by hCG-activated PBMC helps patients with unexplained RIF to reach implantation.

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OX40L/OX40 Signal Promotes IL-9 Production by Mucosal MAIT Cells During Helicobacter pylori Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.626017 ◽

2021 ◽

Vol 12 ◽

Author(s):

Siqi Ming ◽

Mei Zhang ◽

Zibin Liang ◽

Chunna Li ◽

Jianzhong He ◽

...

Keyword(s):

Helicobacter Pylori ◽

Potential Role ◽

Critical Role ◽

Underlying Mechanism ◽

Mucosal Inflammation ◽

Cross Linking ◽

Mait Cells ◽

H Pylori ◽

Mait Cell

Mucosal associated invariant T (MAIT) cells play a critical role in Helicobacter pylori (H. pylori)-induced gastritis by promoting mucosal inflammation and aggravating mucosal injuries (1, 2). However, the underlying mechanism and key molecules involved are still uncertain. Here we identified OX40, a co-stimulatory molecule mainly expressed on T cells, as a critical regulator to promote proliferation and IL-9 production by MAIT cells and facilitate mucosal inflammation in H. pylori-positive gastritis patients. Serum examination revealed an increased level of IL-9 in gastritis patients. Meanwhile, OX40 expression was increased in mucosal MAIT cells, and its ligand OX40L was also up-regulated in mucosal dendritic cells (DCs) of gastritis patients, compared with healthy controls. Further results demonstrated that activation of the OX40/OX40L pathway promoted IL-9 production by MAIT cells, and MAIT cells displayed a highly-activated phenotype after the cross-linking of OX40 and OX40L. Moreover, the level of IL-9 produced by MAIT cells was positively correlated with inflammatory indexes in the gastric mucosa, suggesting the potential role of IL-9-producing MAIT cells in mucosal inflammation. Taken together, we elucidated that OX40/OX40L axis promoted mucosal MAIT cell proliferation and IL-9 production in H. pylori-induced gastritis, which may provide potential targeting strategies for gastritis treatment.

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The role of G-CSF in recurrent implantation failure: A randomized double blind placebo control trial

International Journal of Reproductive BioMedicine ◽

10.29252/ijrm.14.12.737 ◽

2016 ◽

Vol 14 (12) ◽

pp. 737-742 ◽

Cited By ~ 11

Author(s):

Fatemeh Davari-tanha ◽

Ensieh Shahrokh Tehraninejad ◽

Mohadese Ghazi ◽

Zahra Shahraki ◽

◽

...

Keyword(s):

Placebo Control Trial ◽

Placebo Control ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Double Blind ◽

Double Blind Placebo

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Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: A possible role of the sirtuin 1 pathway

Journal of Obstetrics and Gynaecology Research ◽

10.1111/jog.12252 ◽

2013 ◽

Vol 40 (3) ◽

pp. 770-778 ◽

Cited By ~ 28

Author(s):

Ayumi Taguchi ◽

Osamu Wada-Hiraike ◽

Kei Kawana ◽

Kaori Koga ◽

Aki Yamashita ◽

...

Keyword(s):

Stromal Cells ◽

Inflammatory Responses ◽

Sirtuin 1 ◽

Endometrial Stromal Cells

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Indian study shows that encouraging knowledge sharing at work can help spark innovative behavior

Human Resource Management International Digest ◽

10.1108/hrmid-04-2021-0093 ◽

2021 ◽

Vol ahead-of-print (ahead-of-print) ◽

Keyword(s):

Explicit Knowledge ◽

Manufacturing Sector ◽

Critical Role ◽

Underlying Mechanism ◽

Innovative Behavior ◽

Content Type ◽

Indian Manufacturing Sector ◽

Implicit And Explicit ◽

The Relationship

Purpose The authors wanted to find out the most important mechanisms for encouraging innovative behavior in the Indian manufacturing sector. Design/methodology/approach The researchers collected data from Indian manufacturing organizations. They distributed questionnaires and received 288 complete ones. Items measured critical concepts. For OJ one example was “I have been fairly rewarded for the effort I put forth”. For KS, one sample was, “When I have learned something new, I tell my colleagues about it” and, “When they have learned something new, my colleagues tell me about it”. Meanwhile, IB was measured using items such as “I generate original solutions for problems”. Findings It highlighted the pivotal role of OJ in bolstering employees’ IB. When companies treat employees fairly, it encourages positive social interactions that lead to perceptions of supportiveness and trustworthiness. Employees reciprocate these sentiments with positive behavior. The study also showed the positive predictive influence of KS on IB. Finally, the results showed that the relationship between OJ and IB is complex, but KS is a pivotal mediator. Promotion of OJ, KS and IM is “vital” to spark innovation. Originality/value The authors felt their most important finding was to highlight the critical role of the underlying mechanism of KS, which is where individuals exchange implicit and explicit knowledge to create new knowledge. In addition, previous researchers have looked at the role of organizational justice in encouraging innovative behavior, but evidence from non-Western countries is scarce.

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P–388 Endometrial extracellular vesicles from recurrent implantation failure patients inhibited embryonic growth and implantation via miR–6131/PAK2 pathway

Human Reproduction ◽

10.1093/humrep/deab130.387 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

C Liu

Keyword(s):

Extracellular Vesicles ◽

Migration And Invasion ◽

Hatching Rate ◽

Implantation Failure ◽

Trophoblast Cells ◽

Recurrent Implantation Failure ◽

Endometrial Cells ◽

Blastocyst Rate ◽

Fertile Women

Abstract Study question Could endometrial extracellular vesicles from recurrent implantation failure patients (RIF-EVs) attenuate the growth and implantation potentials of embryos and what are the mechanisms? Summary answer: RIF-EVs inhibited embryonic growth and decreased the trophoblast functions via miR–6131/PAK2 pathway. What is known already Recurrent implantation failure (RIF) is characterized by repeated embryo transfers without pregnancy. To date, the etiology of RIF remains poorly understood. Recent evidence indicated that extracellular vesicles (EVs) secreted by endometrial cells, played a crucial role in the implantation by regulating the development and implantation of embryos. Study design, size, duration Endometrial cells isolated from endometrial tissues of RIF patients (n = 25) and fertile women (n = 16) were cultured and modulated via hormones. Endometrial EVs from RIF patients (RIF-EVs) or fertile women (FER-EVs) were isolated from the conditioned medium. The influence of EVs on embryonic development and implantation was investigated by co-culture models of EVs and 2-cell murine embryos or HTR8/SVneo cells, respectively. High-through put sequencing was performed to identify the miRNA profile in the RIF-EVs. Participants/materials, setting, methods RIF-EVs and FER-EVs were characterized using western blotting, nanoparticle tracking analysis, and transmission electron microscopy. After co-culture with EVs, embryonic blastocyst rate and hatching rate were calculated. Besides, the proliferation, migration, and invasion of EV-treated trophoblast cells were evaluated by CCK–8, wound healing, and transwell invasion assays. miRNA expression profiles were compared between RIF-EVs and FER-EVs, and the regulatory role of significantly upregulated miR–6131 in RIF-EVs was investigated in the trophoblast cells. Main results and the role of chance RIF-EVs and FER-EVs are round bilayer vesicles, ranging mainly at 100 nm and enriched in TSG101, Alix, and CD9. Both RIF-EVs and FER-EVs entered embryonic or trophoblast cytoplasm. The blastocyst rate in the RIF-EV groups was significantly decreased compared to that in the FER-EV groups, at concentrations of 5, 10, and 20 μg/ml. The hatching rate was decreased significantly in embryos treated with 10 or 20 μg/ml RIF-EVs compared to those treated with FER-EVs at the same concentration (p < 0.05). The proliferation, migration, and invasion of trophoblasts were significantly decreased in the RIF-EV group at 20 μg/mL. A total of 11 differently expressed (fold change >2 and p < 0.05) miRNAs were found in the RIF-EVs, and two of them were validated in a larger set of EV samples using RT-PCR. The most significantly different miRNA, 6131, was increased in the RIF-EV-treated HTR8/SVneo cells. The up-regulation of miR–6131 inhibited the growth and invasion of HTR8/SVneo. Bioinformatics coupled with luciferase and western blot assays revealed that PAK2 is a direct target of miR–6131, and the overexpression of PAK2 can rescue the phenotype changes induced by miR–6131 overexpression. Limitations, reasons for caution Our study indicated miRNA in the RIF-EVs dysregulating the growth and function of embryonic cells. However, EVs contained a wide spectrum of bioactive molecules, including proteins, mRNAs, and DNA, which may play an important role in the implantation. Further studies are required to investigate the mechanisms. Wider implications of the findings: This work indicates an important role of EVs from women with RIF in embryonic implantation, potentially providing a novel insight to understand the pathophysiology of RIF. Trial registration number Not applicable

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