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Integrated miRNA-seq analysis reveals the molecular mechanism underlying the effect of acupuncture on endometrial receptivity in patients undergoing fertilization: embryo transplantation.

ABSTRACT: Endometrial receptivity (ER) is the main factor affecting in vitro fertilization (IVF) and embryo transplantation. Previous studies have shown that acupuncture might be useful for increasing ER. However, the underlying microRNA (miRNA) molecular mechanisms deserve to be further elucidated. In this study, we performed small RNA sequencing of endometrial samples from infertile women who either underwent acupuncture therapy or did not. Differentially expressed microRNAs (DEmiRNAs) were identified and used to predict target genes. Then, the functional and pathway were analyzed for the target genes. Moreover, quantitative reverse transcription PCR (qRT-PCR) was performed to validate the RNA-seq results. Finally, the miRNA-gene network was conducted by Cytoscape. A total of 39 DEmiRNAs were identified between the acupuncture group and the control group. The functional enrichment analysis suggested that the target genes of the DEmiRNAs were significantly enriched in GO biological process (BP) terms associated with transcription, such as regulation of DNA-templated transcription and positive regulation of DNA-templated transcription. The pathway analysis showed that DEmiRNAs might be involved in acupuncture therapy via Endocytosis, Axon guidance, Oxytocin signaling, the Hippo pathway, and Estrogen signaling pathways. Significant downregulation of hsa-miR-449a and hsa-miR-449b-3p, and significant upregulation of hsa-miR-3135b and hsa-miR-345-3p in the RNA-seq results were validated by qRT-PCR. Besides, these four DEmiRNAs and their 34 target genes conducted a miRNA-gene network. Our results predict that hsa-miR-449a, hsa-miR-3135b and hsa-miR-345-3p may underly mechanisms by which acupuncture therapy help increase ER and promote endometrium receptivity in preparation for in vitro fertilization and embryo transplantation.

SUBMITTER: Mu Y

PROVIDER: S-EPMC6879696 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Integrated miRNA-seq analysis reveals the molecular mechanism underlying the effect of acupuncture on endometrial receptivity in patients undergoing fertilization: embryo transplantation.

Mu Yanyun Y Li Qian Q Cheng Jie J Shen Jie J Jin Xun X Xie Zhengyun Z Gao Zhao Z Zhang Wenjing W Hua Qixin Q Xia Liangjun L Gao Youling Y Xia Youbing Y

3 Biotech 20191127 1

Endometrial receptivity (ER) is the main factor affecting in vitro fertilization (IVF) and embryo transplantation. Previous studies have shown that acupuncture might be useful for increasing ER. However, the underlying microRNA (miRNA) molecular mechanisms deserve to be further elucidated. In this study, we performed small RNA sequencing of endometrial samples from infertile women who either underwent acupuncture therapy or did not. Differentially expressed microRNAs (DEmiRNAs) were identified a ...[more]

PMID: 31824817

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Project description:BackgroundA successful pregnancy using in vitro fertilization and embryo transfer (IVF-ET) requires a receptive endometrium, good-quality embryos, and a synchronized embryo-endometrial dialogue. Although embryo quality and endometrial receptivity (ER) have been fully assessed to exclude substandard conditions, the probability of successful ET is relatively low. Currently, embryo-endometrial synchrony is considered to be a possible explanation, because delayed, advanced, or narrowed window of implantation (WOI) may lead to ET failure.ObjectiveThis study aims to establish a nomogram incorporating a series of ultrasonic ER markers on the day before implantation to assess the embryo-endometrial synchrony, which may contribute to the improvement of clinical pregnancy outcomes.MethodsTotally 583 women with 1135 complete IVF cycles were retrospectively analyzed. Among them, 357 women with 698 cycles and 226 women with 437 cycles were assigned to the training and validation cohorts, respectively. Ultrasonic ER markers obtained on the day before implantation were collected for analyses. In the training cohort, the screened correlates of clinical pregnancy failure were utilized to develop a nomogram for determining whether an infertile woman is suitable for the ET next day. This model was validated both in the training and validation cohorts.ResultsSpiral artery (SA) resistance index (RI), vascularisation index (VI), and flow index (FI) were independently associated with the ET failure (all P < 0.05). They were served as the components of the developed nomogram to visualize the likelihood of implantation failure in IVF-ET. This model was validated to present good discrimination and calibration, and obtained clinical net benefits both in the training and validation cohorts.ConclusionWe developed a nomogram that included SA-RI, VI, and FI on the day before implantation. It may assist physicians to identify patients with displaced WOI, thus avoiding meaningless ET prior to implantation.

Project description:BackgroundReceptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse.ResultsHigh throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited.ConclusionsThis study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.

Project description:Background: Currently, more and more subfertility couples are opting for combined acupuncture to improve the success rate of in vitro fertilization and embryo transfer (IVF-ET). However, the efficacy and safety of acupuncture in IVF-ET is still highly controversial. Objectives: The purpose of this overview is to summarize evidence of essential outcomes of systematic reviews (SRs) of acupuncture in IVF-ET and evaluate their methodological quality. Methods: We conducted a comprehensive literature search for relevant SRs in eight databases from inception to July 31, 2020, without language restriction. We evaluated the methodological quality of the included SRs by using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), which was the latest available assessment tool. The Risk of Bias in Systematic Review (ROBIS) tool was used to assess the risk of bias in SRs. We assessed the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) score to determine the strength of evidence. We excluded the overlapping randomized controlled trials (RCTs) and performed a re-meta-analysis of the primary RCTs. Results: This review included 312 original RCT studies and 65,388 participants. By using AMSTAR-2, we found that the methodological quality of 16 SRs was critically low, because they had more than one critical weakness. Our reviews showed that although the GRADE for quality of evidence profile was suboptimal, acupuncture seemed to be beneficial in increasing the pregnancy rate. Our re-meta-analysis suggested that acupuncture was superior to sham acupuncture in improving the clinical pregnancy rate (CPR) of IVF-ET with substantial heterogeneity (RR = 1.31, 95% CI: 1.13-1.52, p = 0.0004, I 2 = 66%). No statistical difference was observed regarding the outcomes of live birth rate (LBR), ongoing pregnancy rate (OPR), biochemical pregnancy rate (BPR), and miscarriage rate (MR) between two groups. When compared with no adjunctive treatment groups, acupuncture improved CPR (RR = 1. 25, 95% CI: 1.11-1.42, p = 0.0003) and OPR (RR = 1. 38, 95% CI: 1.04-1.83, p = 0.03). Acupuncture was more superior than no adjunctive treatment in reducing MR (OR = 1.42, 95% CI: 1.03-1.95, p = 0.03) and BPR (RR = 1.19, 95% CI: 1.02-1.37, p = 0.02). Conclusions: Although the evidence of acupuncture in IVF-ET is insufficient, acupuncture appears to be beneficial to increase the clinical pregnancy rate in women undergoing IVF-ET. However, there are severe heterogeneity and methodological quality defects, which limit the reliability of results. Further, high-quality primary studies are still needed.

Project description:MiR-145 is reported to facilitate inflammation and is also associated with unsuccessful embryonic implantation. Whether miR-145 mediates inflammatory response underlying hydrosalpinx-induced defective endometrial receptivity (ER) remains unclear, and this study attempted to clarify this point. Endometrium samples were collected from hydrosalpinx patients (case, n = 243) and patients with tubal patency/obstruction (control, n = 187). The peripheral blood samples of cases and controls were collected to determine the genotypes of miR-145 SNPs. The value of miR-145 expression in the diagnosis and prognostic estimation of hydrosalpinx was assessed using ROC curve and regression analysis, respectively. Lipopolysaccharide (LPS) cell model was established with endometrial cells, and cells were transfected with miR-145 mimic, inhibitor, or negative control. MiR-145 and cytokine levels were quantified by quantitative reverse transcription PCR or western blot. MiR-145 expression was significantly higher in hydrosalpinx compared to control group, and high miR-145 expression was significantly associated with moderate/severe tube lesion, high pulsatility index (>1.06), and high resistance index (>0.61) in hydrosalpinx patients. ROC curve analysis indicated that monitoring miR-145 expression may be useful for the diagnosis of hydrosalpinx (AUC = 0.704). A alleles of rs41291957 (G>A) and rs353292 (G>A) were significantly associated with an increased risk of hydrosalpinx compared to G allele (p < 0.05), yet the mutant allele of rs353291 (A>G) and rs4705343 (T>C) significantly reduced susceptibility to hydrosalpinx compared to the wild type allele. Treatments with miR-145 mimic and LPS in endometrial cells significantly increased the levels of transforming growth factor-?1, tumor necrosis factor -?, interleukin (IL)-6, and IL-8 compared to negative control, while treatment with miR-145 inhibitor decreased the cytokine levels. In conclusion, abnormally expressed miR-145 may be involved in hydrosalpinx-induced ER defects by regulating the inflammatory response.

Dataset Information

Integrated miRNA-seq analysis reveals the molecular mechanism underlying the effect of acupuncture on endometrial receptivity in patients undergoing fertilization: embryo transplantation.

Publications

Integrated miRNA-seq analysis reveals the molecular mechanism underlying the effect of acupuncture on endometrial receptivity in patients undergoing fertilization: embryo transplantation.

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