PAEP and cilia gene splicing changes in endometrial glands during the implantation window in women with recurrent pregnancy loss

ABSTRACTEndometrial glands are essential for fertility, consisting of ciliated and secretory cells that facilitate a suitable uterine environment for embryo implantation. This study sought to determine whether an endometrial gland specific transcriptome and splicing profile are altered in women with recurrent pregnancy loss. Our data provide a comprehensive catalogue of cilia and PAEP gene isoforms and relative exon usage in endometrial glands. We report a previously unannotated endometrial gland cilia transcript GALNT11 and its susceptibility to exon skipping. Key endometrial receptivity gene transcripts are also reported to change in endometrial glands of women with recurrent pregnancy loss. The endometrial gland cilia and PAEP targets identified in this study could be used to identify a perturbed endometrium, isolate causes of recurrent pregnancy loss and develop targeted therapies in personalised medicine.

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Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress

Reproduction ◽

10.1530/rep-19-0391 ◽

2020 ◽

Vol 159 (4) ◽

pp. R203-R211 ◽

Cited By ~ 3

Author(s):

Elizabeth Soczewski ◽

Esteban Grasso ◽

Lucila Gallino ◽

Vanesa Hauk ◽

Laura Fernández ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Inflammatory Response ◽

Er Stress ◽

Stromal Cells ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Endometrial Stromal Cells ◽

Unfolded Protein ◽

Protein Response

Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).

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P–555 Recurrent pregnancy loss is associated with changes in the pre-pregnant endometrial gland transcriptome

Human Reproduction ◽

10.1093/humrep/deab130.554 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

J Pearson-Farr ◽

R Lewis ◽

J Cleal ◽

Y Cheong

Keyword(s):

Gene Expression ◽

Observational Study ◽

Differential Gene Expression ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Small Sample ◽

Specific Cell ◽

Endometrial Gland ◽

Egg Donor ◽

Differential Gene

Abstract Study question Do endometrial gland factors influence recurrent pregnancy loss? Summary answer The endometrial gland transcriptome during the window of implantation is altered in women with recurrent pregnancy loss compared to controls. What is known already Secretions from endometrial glands contribute to the uterine environment that supports the attachment and implantation of the embryo in early pregnancy. Studies have attempted to identify an endometrial gene expression pattern associated with recurrent pregnancy loss however, the cellular heterogeneity within the endometrium may obscure important differences in specific cell populations. Study design, size, duration An observational study comparing controls and women with recurrent pregnancy loss. Participants/materials, setting, methods Endometrial samples were collected during the implantation period of the menstrual cycle from five matched participant egg donor controls and women with recurrent pregnancy loss. Endometrial glands were isolated from fresh endometrial biopsies and RNA sequencing was performed. A differential gene expression analysis and a gene ontology enrichment analysis was performed between egg donor controls and women with recurrent pregnancy loss. Main results and the role of chance This study reports a glandular epithelium specific gene expression profile and demonstrates differential gene expression of endometrial glands from women with recurrent pregnancy loss compared to controls. 18 genes were upregulated and 1 gene was downregulated in the endometrial glands from women with recurrent pregnancy loss compared to controls (5% false discovery rate). Biological processes which contain genes that were differentially expressed in women with recurrent pregnancy loss compared to controls include epithelial cell migration and regulation of secretion by the cell. Limitations, reasons for caution This is an observational study with a relatively small sample size. Wider implications of the findings: This study identified differences in gene expression in women with recurrent pregnancy loss that are specifically associated with endometrial glands rather than endometrium as a whole. These differences could be used to identify a perturbed endometrium, isolate causes of recurrent pregnancy loss and develop targeted therapies. Trial registration number Not applicable

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Expression of ADAMTS13 in human endometrium and its potential role in recurrent pregnancy loss

Archives of Medical Science ◽

10.5114/aoms/133138 ◽

2021 ◽

Author(s):

Yun Feng ◽

Xueyin Li ◽

Xi Chen ◽

Mengling Zhao ◽

Qian Wang ◽

...

Keyword(s):

Pregnancy Loss ◽

Molecular Mechanisms ◽

Recurrent Pregnancy Loss ◽

Gene Knockout ◽

Embryo Implantation ◽

Human Endometrium ◽

Control Group ◽

Expression Levels ◽

Knockout Animal ◽

Mrna And Protein Expression

IntroductionThe mechanisms underlying the pathogenesis of recurrent pregnancy loss (RPL) and the effective approaches to treat this disease still remain vague and absent. Proteinases of ADAMTS family play important roles in embryonic growth and development. Our previous study suggest a role of ADAMTS13 during pregnancy. Current Study was to determine the expression of ADAMTS13 in human endometrium and its association with RPL.Material and methodsThe spatiotemporal expression of ADAMTS13 in human endometrium was examined by immunohistochemistry. real-time PCR sand western blot were then employed to determine the mRNA and protein expression levels of ADAMTS13 in human endometrium. Proteolytic cleavage of FRETS-VWF73 were performed to determine the activity of ADAMTS13 in plasma and that secreted by human endometrium. ELISA was carried out to measure plasma VWF antigen.ResultsWe show that proteolytically active ADAMTS13 is expressed in human endometrium throughout the menstrual cycle and pregnancy. The decidual expression levels of mRNA and protein in women with RPL were significantly lower compared with women with uncomplicated pregnancies (P<0.01, P<0.05, respectively). Furthermore, significantly reduced plasma ADAMTS13 activity (median [range] 69.09 [65.2–93.7]% versus 93.62 [88.1–115.6]%, P<0.001) and elevated plasma VWF antigen levels (median [range] of 125.5 [54.2–262.8]% versus 91.9[80.4–138.7]%, P < 0.01) were detected in RPL patients compared with the control group.ConclusionsThese findings suggest that ADAMTS13 may play a role in embryo implantation and the pathogenesis of recurrent pregnancy loss. Further investigation on ADAMTS13 gene knockout animal models is necessary for understanding the molecular mechanisms of the biological roles of ADAMTS13 during gestation.

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Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

Seminars in Reproductive Medicine ◽

10.1055/s-0039-3400966 ◽

2019 ◽

Vol 37 (04) ◽

pp. 182-190 ◽

Cited By ~ 2

Author(s):

Sally Radovick ◽

Andy V. Babwah

Keyword(s):

Stromal Cells ◽

Pregnancy Loss ◽

Therapeutic Agent ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Extravillous Trophoblast ◽

Migration And Invasion ◽

Decidual Cell ◽

Signaling Systems ◽

Placental Invasion

AbstractSeveral studies provide strong evidence suggesting that in addition to central kisspeptin/KISS1R signaling, the peripheral uterine- and placental-based kisspeptin/KISS1R signaling systems are major regulators of pregnancy. Specifically, the evidence suggests that the uterine-based system regulates embryo implantation and decidualization, while both the uterine- and placental-based systems regulate placentation. Uterine kisspeptin and KISS1R regulate embryo implantation by controlling the availability of endometrial glandular secretions, like leukemia inhibitory factor, which are essential for embryo adhesion to the uterine epithelium. As for decidualization, the data suggest that decidualized stromal cells express KISS1R and secrete kisspeptin-inhibiting decidual cell motility and thereby indirectly regulate embryo and placental invasion of the uterus. Similarly, for placentation, placental kisspeptin and KISS1R negatively regulate extravillous trophoblast migration and invasion and thereby directly control placental invasion of the uterus. Having recognized a significant role for the uterine- and placental-based kisspeptin/KISS1R signaling systems regulating pregnancy, the future looks promising for the development of kisspeptin and KISS1R as prognostic and diagnostic markers of pregnancy disorders and the use of kisspeptin as a therapeutic agent in the prevention and treatment of conditions such as recurring implantation failure, recurrent pregnancy loss, and preeclampsia.

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The Male Factor in Recurrent Pregnancy Loss and Embryo Implantation Failure

Recurrent Pregnancy Loss ◽

10.1201/b17855-38 ◽

2014 ◽

pp. 320-331

Keyword(s):

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Implantation Failure ◽

Male Factor

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Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model

Reproductive Sciences ◽

10.1177/1933719119828110 ◽

2019 ◽

Vol 26 (12) ◽

pp. 1545-1556 ◽

Cited By ~ 2

Author(s):

Greene Donald Royster ◽

Justine C. Harris ◽

Amanda Nelson ◽

Yessenia Castro ◽

R. Patrick Weitzel ◽

...

Keyword(s):

Murine Model ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Mammalian Target Of Rapamycin ◽

Unexplained Infertility ◽

Implantation Failure ◽

T Regulatory Cell ◽

Recurrent Implantation Failure ◽

Regulatory Cell

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (Treg) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4+CD25+FoxP3+ Tregs from donors improves litter sizes in DEREG mice with depleted Tregs. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete Tregs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase Tregs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of Tregs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of Tregs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low Treg.

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DNA Methylation and Recurrent Pregnancy Loss: A Mysterious Compass?

Frontiers in Immunology ◽

10.3389/fimmu.2021.738962 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qi Zhou ◽

Yunhe Xiong ◽

Bing Qu ◽

Anyu Bao ◽

Yan Zhang

Keyword(s):

Dna Methylation ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Research Progress ◽

Immune Microenvironment ◽

Personalized Diagnosis ◽

New Perspective ◽

Immune Related Genes ◽

Cellular Components

Recurrent pregnancy loss (RPL) is a common and severe pathological pregnancy, whose pathogenesis is not fully understood. With the development of epigenetics, the study of DNA methylation, provides a new perspective on the pathogenesis and therapy of RPL. The abnormal DNA methylation of imprinted genes, placenta-specific genes, immune-related genes and sperm DNA may, directly or indirectly, affect embryo implantation, growth and development, leading to the occurrence of RPL. In addition, the unique immune tolerogenic microenvironment formed at the maternal-fetal interface has an irreplaceable effect on the maintenance of pregnancy. In view of these, changes in the cellular components of the maternal-fetal immune microenvironment and the regulation of DNA methylation have attracted a lot of research interest. This review summarizes the research progress of DNA methylation involved in the occurrence of RPL and the regulation of the maternal-fetal immune microenvironment. The review provides insights into the personalized diagnosis and treatment of RPL.

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