The endoplasmic reticulum protein HSPA5/BiP is essential for decidual transformation of human endometrial stromal cells.

Decidualization denotes the process of inflammatory reprogramming of endometrial stromal cells (EnSC) into specialized decidual cells (DC). During this process, EnSC are subjected to endoplasmic reticulum (ER) stress as well as acute cellular senescence. Both processes contribute to the proinflammatory mid-luteal implantation window and their dysregulation has been implicated in reproductive failure.

Dynamic chromatin remodeling in cycling human endometrium at single-cell level.

Estrogen-dependent proliferation followed by progesterone-dependent differentiation of the endometrium culminates in a short implantation window. We performed single-cell assay for transposase-accessible chromatin with sequencing on endometrial samples obtained across the menstrual cycle to investigate the regulation of temporal gene networks that control embryo implantation. We identify uniquely accessible chromatin regions in all major cellular constituents of the endometrium, delineate temporal patterns of coordinated chromatin remodeling in epithelial and stromal cells, and gain mechanistic insights into the emergence of a receptive state through integrated analysis of enriched transcription factor (TF) binding sites in dynamic chromatin regions, chromatin immunoprecipitation sequencing analyses, and gene expression data.

Human embryo implantation.

Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans.

The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage.

In each menstrual cycle, the endometrium becomes receptive to embryo implantation while preparing for tissue breakdown and repair. Both pregnancy and menstruation are dependent on spontaneous decidualization of endometrial stromal cells, a progesterone-dependent process that follows rapid, oestrogen-dependent proliferation. During the implantation window, stromal cells mount an acute stress response, which leads to the emergence of functionally distinct decidual subsets, reflecting the level of replication stress incurred during the preceding proliferative phase.

JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain gene repression and is essential for cell differentiation. In low-grade endometrial stromal sarcoma (LG-ESS), the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. We show that JAZF1-SUZ12 dysregulates PRC2 composition, genome occupancy, histone modification, gene expression, and cell differentiation.

EndoTime: non-categorical timing estimates for luteal endometrium.

Study Question: Can the accuracy of timing of luteal phase endometrial biopsies based on urinary ovulation testing be improved by measuring the expression of a small number of genes and a continuous, non-categorical modelling approach?

Summary Answer: Measuring the expression levels of six genes (IL2RB, IGFBP1, CXCL14, DPP4, GPX3 and SLC15A2) is sufficient to obtain substantially more accurate timing estimates and to assess the reliability of timing estimates for each sample.

What Is Known Already: Commercially available endometrial timing approaches based on gene expression require large gene sets and use a categorical approach that classifies samples as pre-receptive, receptive or post-receptive.

Study Design, Size, Duration: Gene expression was measured by RTq-PCR in different sample sets, comprising a total of 664 endometrial biopsies obtained 4-12 days after a self-reported positive home ovulation test.

Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes.

Evolutionary changes in the anatomy and physiology of the female reproductive system underlie the origins and diversification of pregnancy in Eutherian ('placental') mammals. This developmental and evolutionary history constrains normal physiological functions and biases the ways in which dysfunction contributes to reproductive trait diseases and adverse pregnancy outcomes. Here, we show that gene expression changes in the human endometrium during pregnancy are associated with the evolution of human-specific traits and pathologies of pregnancy.

Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC.

Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion . A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood.

Acute atherosis and diffuse lipid infiltration of the placental bed: A review of historical lipid studies.

Based on a variety of tissue samples, including Caesarean hysterectomy specimens with the placenta in situ, a detailed map of uteroplacental vascular lesions was established in over a century of research. One such lesion is acute atherosis of unremodelled basal and uteroplacental arteries, defined by the presence of fibrinoid necrosis, subendothelial macrophage foam cells, and perivascular lymphocytic infiltration. Two studies conducted over 50 years ago used Oil Red O staining of frozen tissue sections to visualise lipid infiltration of placental bed vessels and document the presence of lipid-laden foam cells in acute atherosis.

Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window.

During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC).

Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial.

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial.

Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells.

Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties.

Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries.

We explore the potential role of the endothelial lining of uteroplacental arteries in the pathogenesis of preeclampsia, a severe pregnancy disorder characterized by incomplete invasion of the uterine vasculature by extravillous trophoblast and angiogenic imbalance. In normal pregnancy, the endothelium disappears progressively from the uteroplacental arteries and is replaced by trophoblast and deposition of fibrofibrinoid structure, underpinning the so-called physiological transformation of uterine spiral arteries. We hypothesize that partial persistence of the endothelium, albeit injured, initiates a chain of events leading to the emergence of preeclampsia in 3 sequential stages.

Covalent Attachment of Fibronectin onto Emulsion-Templated Porous Polymer Scaffolds Enhances Human Endometrial Stromal Cell Adhesion, Infiltration, and Function.

A novel strategy for the surface functionalization of emulsion-templated highly porous (polyHIPE) materials as well as its application to in vitro 3D cell culture is presented. A heterobifunctional linker that consists of an amine-reactive N-hydroxysuccinimide ester and a photoactivatable nitrophenyl azide, N-sulfosuccinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate (sulfo-SANPAH), is utilized to functionalize polyHIPE surfaces. The ability to conjugate a range of compounds (6-aminofluorescein, heptafluorobutylamine, poly(ethylene glycol) bis-amine, and fibronectin) to the polyHIPE surface is demonstrated using fluorescence imaging, FTIR spectroscopy, and X-ray photoelectron spectroscopy.

Adolescent Preeclampsia: Pathological Drivers and Clinical Prevention.

Preeclampsia is an important cause of maternal and perinatal morbidity, especially in first-time pregnant adolescent women. Although prevention of preeclampsia has been attempted for many decades, effective intervention can only be achieved upon the full elucidation of the risk factors and mechanisms of disease. As the pathogenesis of preeclampsia during adolescence may differ from that in older women, preventive interventions should be tailored accordingly.

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association.

The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif.

Analysis of chromatin accessibility in decidualizing human endometrial stromal cells.

Spontaneous decidualization of the endometrium in response to progesterone signaling is confined to menstruating species, including humans and other higher primates. During this process, endometrial stromal cells (EnSCs) differentiate into specialized decidual cells that control embryo implantation. We subjected undifferentiated and decidualizing human EnSCs to an assay for transposase accessible chromatin with sequencing (ATAC-seq) to map the underlying chromatin changes.

The Glycosyltransferase EOGT Regulates Adropin Expression in Decidualizing Human Endometrium.

In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity of the fetomaternal interface and, by extension, survival of the conceptus. O-GlcNAcylation is an essential posttranslational modification that links glucose sensing to cellular stress resistance. Unexpectedly, decidualization of primary endometrial stromal cells (EnSCs) was associated with a 60% reduction in O-linked β-N-acetylglucosamine (O-GlcNAc)‒modified proteins, reflecting downregulation of the enzyme that adds O-GlcNAc to substrates (O-GlcNAc transferase; OGT) but not the enzyme that removes the modification (O-GlcNAcase).

Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium.

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner.

Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption.

BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse.

The impact of uterine immaturity on obstetrical syndromes during adolescence.

Pregnant nulliparous adolescents are at increased risk, inversely proportional to their age, of major obstetric syndromes, including preeclampsia, fetal growth restriction, and preterm birth. Emerging evidence indicates that biological immaturity of the uterus accounts for the increased incidence of obstetrical disorders in very young mothers, possibly compounded by sociodemographic factors associated with teenage pregnancy. The endometrium in most newborns is intrinsically resistant to progesterone signaling, and the rate of transition to a fully responsive tissue likely determines pregnancy outcome during adolescence.

Reprogramming of the retinoic acid pathway in decidualizing human endometrial stromal cells.

Upon breaching of the endometrial surface epithelium, the implanting embryo embeds in the decidualizing stroma. Retinoic acid (RA), a metabolite of vitamin A, is an important morphogen during embryonic and fetal development, although the role of the RA pathway in the surrounding decidual cells is not understood. Here we show that decidual transformation of human endometrial stromal cells (HESCs) results in profound reprogramming of the RA signaling and metabolism pathways.

Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells.

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage.