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Uterine DCs are crucial for decidua formation during embryo implantation in mice.

ABSTRACT: Implantation is a key stage during pregnancy, as the fate of the embryo is often decided upon its first contact with the maternal endometrium. Around this time, DCs accumulate in the uterus; however, their role in pregnancy and, more specifically, implantation, remains unknown. We investigated the function of uterine DCs (uDCs) during implantation using a transgenic mouse model that allows conditional ablation of uDCs in a spatially and temporally regulated manner. Depletion of uDCs resulted in a severe impairment of the implantation process, leading to embryo resorption. Depletion of uDCs also caused embryo resorption in syngeneic and T cell-deficient pregnancies, which argues against a failure to establish immunological tolerance during implantation. Moreover, even in the absence of embryos, experimentally induced deciduae failed to adequately form. Implantation failure was associated with impaired decidual proliferation and differentiation. Dynamic contrast-enhanced MRI revealed perturbed angiogenesis characterized by reduced vascular expansion and attenuated maturation. We suggest therefore that uDCs directly fine-tune decidual angiogenesis by providing two critical factors, sFlt1 and TGF-beta1, that promote coordinated blood vessel maturation. Collectively, uDCs appear to govern uterine receptivity, independent of their predicted role in immunological tolerance, by regulating tissue remodeling and angiogenesis. Importantly, our results may aid in understanding the limited implantation success of embryos transferred following in vitro fertilization.

SUBMITTER: Plaks V

PROVIDER: S-EPMC2582932 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Aberrant uterine folding in mice disrupts implantation chamber formation and alignment of embryo-uterine axes.

Project description:The uterine luminal epithelium folds characteristically in mammals, including humans, horses and rodents. Improper uterine folding in horses results in pregnancy failure, but the precise function of folds remains unknown. Here, we uncover dynamic changes in the 3D uterine folding pattern during early pregnancy with the entire lumen forming pre-implantation transverse folds along the mesometrial-antimesometrial axis. Using a time course, we show that transverse folds are formed before embryo spacing, whereas implantation chambers form as the embryo begins attachment. Thus, folds and chambers are two distinct structures. Transverse folds resolve to form a flat implantation region, after which an embryo arrives at its center to attach and form the post-implantation chamber. Our data also suggest that the implantation chamber facilitates embryo rotation and its alignment along the uterine mesometrial-antimesometrial axis. Using WNT5A- and RBPJ-deficient mice that display aberrant folds, we show that embryos trapped in longitudinal folds display misalignment of the embryo-uterine axes, abnormal chamber formation and defective post-implantation morphogenesis. These mouse models with disrupted uterine folding provide an opportunity to understand uterine structure-based mechanisms that are crucial for implantation and pregnancy success. This article has an associated 'The people behind the papers' interview.

| S-EPMC9245188 | biostudies-literature

EMBRYO-UTERINE INTERACTION COORDINATES MOUSE EMBRYOGENESIS DURING IMPLANTATION

Project description:Embryo implantation into the uterus marks a key transition in mammalian development. In mice, implantation is mediated by the trophoblast and is accompanied by a morphological transition from the blastocyst to the egg cylinder. However, the roles of trophoblast-uterine interactions in embryo morphogenesis during implantation are poorly understood due to inaccessibility in utero and the remaining challenges to recapitulate it ex vivo from the blastocyst. Here, we engineer a uterus-like microenvironment to recapitulate peri-implantation development of the whole mouse embryo ex vivo and reveal essential roles of the physical embryo-uterine interaction. We demonstrate that adhesion between the trophoblast and the uterine matrix is required for in utero-like transition of the blastocyst to the egg cylinder. Modeling the implanting embryo as a wetting droplet links embryo shape dynamics to the underlying changes in trophoblast adhesion and suggests that the adhesion-mediated tension release facilitates egg cylinder formation. Light-sheet live imaging and the experimental control of the engineered uterine geometry and trophoblast velocity uncovers the coordination between trophoblast motility and embryo growth, where the trophoblast delineates space for embryo morphogenesis.

| S-SCDT-10_15252-EMBJ_2022113280 | biostudies-other

Heparan Sulfate Proteoglycan Sulfation Regulates Uterine Differentiation and Signaling During Embryo Implantation.

Project description:To prepare for embryo implantation, the uterus must undergo a series of reciprocal interactions between the uterine epithelium and the underlying stroma, which are orchestrated by ovarian hormones. During this process, multiple signaling pathways are activated to direct cell proliferation and differentiation, which render the uterus receptive to the implanting blastocysts. One important modulator of these signaling pathways is the cell surface and extracellular matrix macromolecules, heparan sulfate proteoglycans (HSPGs). HSPGs play crucial roles in signal transduction by regulating morphogen transport and ligand binding. In this study, we examine the role of HSPG sulfation in regulating uterine receptivity by conditionally deleting the N-deacetylase/N-sulfotransferase (NDST) 1 gene (Ndst1) in the mouse uterus using the Pgr-Cre driver, on an Ndst2- and Ndst3-null genetic background. Although development of the female reproductive tract and subsequent ovarian function appear normal in Ndst triple-knockout females, they are infertile due to implantation defects. Embryo attachment appears to occur but the uterine epithelium at the site of implantation persists rather than disintegrates in the mutant. Uterine epithelial cells continued to proliferate past day 4 of pregnancy, accompanied by elevated Fgf2 and Fgf9 expression, whereas uterine stroma failed to undergo decidualization, as evidenced by lack of Bmp2 induction. Despite normal Indian hedgehog expression, transcripts of Ptch1 and Gli1, both components as well as targets of the hedgehog (Hh) pathway, were detected only in the subepithelial stroma, indicating altered Hh signaling in the mutant uterus. Taken together, these data implicate an essential role for HSPGs in modulating signal transduction during mouse implantation.

| S-EPMC6692868 | biostudies-literature

Uterine Expression of NDRG4 Is Induced by Estrogen and Up-Regulated during Embryo Implantation Process in Mice.

Project description:Embryo implantation is an essential step for the establishment of pregnancy and dynamically regulated by estrogen and progesterone. NDRG4 (N-myc down-regulated gene 4) is a tumor suppressor that participates in cell survival, tumor invasion and angiogenesis. The objective of this study was to preliminarily explore the role of NDRG4 in embryo implantation. By immunohistochemistry (IHC) and quantitive RT-PCR (qRT-PCR), we found that uterine expression of NDRG4 was increased along with puberal development, and its expression in adult females reached the peak at the estrus stage during the estrus cycle. Furthermore, uterine NDRG4 expression was significantly induced by the treatment of estradiol (E2) both in pre-puberty females and ovariectomized adult females. Uterine expression pattern of NDRG4 during the peri-implantation period in mice was determined by IHC, qRT-PCR and Western blot. It was observed that NDRG4 expression was up-regulated during the implantation process, and its expression level at the implantation sites was significantly higher than that at the inter-implantation sites. Meanwhile, an increased expression in NDRG4 was associated with artificial decidualization as well as the activation of delayed implantation. By qRT-PCR and Western blot, we found that the in vitro decidualization of endometrial stromal cells (ESCs) was accompanied by up-regulation of NDRG4 expression, whereas knockdown of its expression in these cells by siRNA inhibited the decidualization process. In addition, Western blot analysis showed that NDRG4 protein expression was decreased in human villus tissues of recurrent miscarriage (RM) patients compared to normal pregnant women. Collectively, these data suggested that uterine NDRG4 expression could be induced by estrogen, and NDRG4 might play an important role during early pregnancy.

| S-EPMC4866685 | biostudies-other

Broad gap junction blocker carbenoxolone disrupts uterine preparation for embryo implantation in mice.

Project description:Gap junctions have an important role in cell-to-cell communication, a process obviously required for embryo implantation. Uterine luminal epithelium (LE) is the first contact for an implanting embryo and is critical for the establishment of uterine receptivity. Microarray analysis of the LE from peri-implantation mouse uterus showed low-level expression of 19 gap junction proteins in preimplantation LE and upregulation of gap junction protein, beta 2 (GJB2, connexin 26, Cx26) in postimplantation LE. Time course study using in situ hybridization and immunofluorescence revealed upregulation of GJB2 in the LE surrounding the implantation site before decidualization. Similar dynamic expression of GJB2 was observed in the LE of artificially decidualized mice but not pseudopregnant mice. To determine the potential function of uterine gap junctions in embryo implantation, carbenoxolone (CBX), a broad gap junction blocker, was injected i.p. (100 mg/kg) or via local uterine fat pad (10 mg/kg) into pregnant mice on Gestation Day 3 at 1800 h, a few hours before embryo attachment to the LE. These CBX treatments disrupted embryo implantation, suggesting local effects of CBX in the uterus. However, i.p. injection of glycyrrhizic acid (100 mg/kg), which shares similar structure and multiple properties with CBX but is ineffective in blocking gap junctions, did not affect embryo implantation. Carbenoxolone also inhibited oil-induced artificial decidualization, concomitant with suppressed molecular changes and ultrastructural transformations associated with uterine preparation for embryo implantation, underscoring the adverse effect of CBX on uterine preparation for embryo implantation. These data demonstrate that uterine gap junctions are important for embryo implantation.

| S-EPMC4076363 | biostudies-literature

Uterine Flushing Fluid-Derived Let-7b Targets CXCL10 to Regulate Uterine Receptivity in Goats during Embryo Implantation.

Project description:Exosomes have the ability to carry a wide range of chemicals, convey them to target cells or target regions, and act as "messengers." For the purpose of investigating embryo attachment, it is helpful to comprehend the range of exosomal mRNAs and miRNAs derived from the uterine flushing fluid before and after embryo attachment. In this study, we recovered exosomes from goat uterine rinsing fluid at 5, 15, and 18 days of gestation and used RNA-Seq to identify the mRNA and miRNA profiles of exosomes obtained from uterine rinsing fluid before and after embryo implantation. In total, 91 differently expressed miRNAs and 27,487 differentially expressed mRNAs were found. The target genes predicted by the differentially expressed miRNAs and the differentially expressed mRNAs were mainly membrane-related organelles with catalytic activity, binding activity, transcriptional regulation activity, and involved in metabolism, biological regulation, development, and other processes. This was revealed by GO analysis. Furthermore, KEGG analysis revealed that they were abundant in signaling pathways associated with embryo implantation, including the "PI3K-Akt signaling pathway," "Toll-like receptor signaling pathway," "TGF-beta signaling route," "Notch signaling pathway," and others. Moreover, our research has demonstrated, for the first time, that chi-let-7b-5p specifically targets the 3'UTR of CXCL10. Our research offers a fresh viewpoint on the mechanics of embryo attachment.

| S-EPMC9917504 | biostudies-literature

MicroRNA-223-3p suppresses leukemia inhibitory factor expression and pinopodes formation during embryo implantation in mice.

Project description:MicroRNA (miRNA) regulates gene expression in a post-transcriptional manner, which hybridizes the target mRNAs with complementary sequence and subsequently leads to translation repression or mRNA degradation. Online sequence alignment showed that there is a putative binding site of miR-223-3p on the 3'UTR of LIF, which is considered to be an important marker of endometrial receptivity. Thus, we hypothesized that miR-223-3p may affect embryo implantation by suppressing LIF expression. In this study, we found that miR-223-3p and LIF protein was inversely expressed in the endometrium of mice during implantation window. Then we proved that miR-223-3p directly binds to LIF 3'UTR with luciferase reporter assay and supresses the expression of LIF. To investigate whether miR-233-3p affects embryo implantation, miR-223-3p agonist was injected into the uteri of pregnant mice. The results demonstrated the suppressing effect of miR-223-3p on embryo implantation. Furthermore, over-expression of miR-223-3p was found to compromise pinopodes formation in the endometrium of mice. Taken all together, our findings revealed that miR-223-3p suppresses pinopodes formation and LIF protein expression, which may lead to diminished embryo implantation.

| S-EPMC4846958 | biostudies-literature

Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming.

Project description:Basement membranes (BMs) are specialized extracellular scaffolds that influence behaviors of cells in epithelial, endothelial, muscle, nervous, and fat tissues. Throughout development and in response to injury or disease, BMs are fine-tuned with specific protein compositions, ultrastructure, and localization. These features are modulated through implements of the BM toolkit that is comprised of collagen IV, laminin, perlecan, and nidogen. Two additional proteins, peroxidasin and Goodpasture antigen-binding protein (GPBP), have recently emerged as potential members of the toolkit. In the present study, we sought to determine whether peroxidasin and GPBP undergo dynamic regulation in the assembly of uterine tissue BMs in early pregnancy as a tractable model for dynamic adult BMs. We explored these proteins in the context of collagen IV and laminin that are known to extensively change for decidualization. Electron microscopic analyses revealed: 1) a smooth continuous layer of BM in between the epithelial and stromal layers of the preimplantation endometrium; and 2) interrupted, uneven, and progressively thickened BM within the pericellular space of the postimplantation decidua. Quantification of mRNA levels by qPCR showed changes in expression levels that were complemented by immunofluorescence localization of peroxidasin, GPBP, collagen IV, and laminin. Novel BM-associated and subcellular spatiotemporal localization patterns of the four components suggest both collective pericellular functions and distinct functions in the uterus during reprogramming for embryo implantation.

| S-EPMC5328942 | biostudies-literature

Decrease in Expression of HOXA10 in the Decidua After Embryo Implantation Promotes Trophoblast Invasion.

Project description:An important step toward successful pregnancy involves invasion of the trophoblast cells into the decidua for placentation. Herein, we show that in the human and baboon decidua HOXA10 expression is downregulated after implantation and that this reduction is most prominent in the decidual cells juxtaposed to the invading placental villi. The supernatants derived from HOXA10-depleted human decidual cells increase the invasiveness of the trophoblast cell lines ACH-3P and JEG3 in vitro; this increase is due to higher expression and activity of matrix metalloproteases (MMPs) and reduced expression of tissue inhibitors of MMPs in both the cell lines. The proinvasive ability of HOXA10-depleted decidual cells is due to increased levels and secretion of leukemia inhibitor factor (LIF) and interleukin (IL)-6. Both these cytokines individually promote invasion of ACH-3P and JEG3 cell by increasing the activities of MMPs and decreasing mRNA levels of TIMPs. Finally, we demonstrate that the supernatants derived from HOXA10-depleted decidual cell-phosphorylated STAT3 (Tyr 705) and knocking down STAT3 in ACH-3P and JEG3 cells restrained the invasion mediated by supernatants derived from HOXA10-depleted decidual cells. These results imply that STAT3 activity is essential and sufficient to promote invasion in response to downregulation of HOXA10 in decidual cells. We propose that downregulation of HOXA10 in the decidual cells promotes the expression of LIF and IL-6, which, in a paracrine manner, activates STAT3 in the trophoblast cells, leading to an increase in MMPs to facilitate invasion.

| S-EPMC6283436 | biostudies-literature

Macrophages regulate corpus luteum development during embryo implantation in mice.

Project description:Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early pregnancy. Macrophage depletion after conception caused embryo implantation arrest associated with diminished plasma progesterone and poor uterine receptivity. Implantation failure was alleviated by administration of bone marrow-derived CD11b+F4/80+ monocytes/macrophages. In the ovaries of macrophage-depleted mice, corpora lutea were profoundly abnormal, with elevated Ptgs2, Hif1a, and other inflammation and apoptosis genes and with diminished expression of steroidogenesis genes Star, Cyp11a1, and Hsd3b1. Infertility was rescued by exogenous progesterone, which confirmed that uterine refractoriness was fully attributable to the underlying luteal defect. In normally developing corpora lutea, macrophages were intimately juxtaposed with endothelial cells and expressed the proangiogenic marker TIE2. After macrophage depletion, substantial disruption of the luteal microvascular network occurred and was associated with altered ovarian expression of genes that encode vascular endothelial growth factors. These data indicate a critical role for macrophages in supporting the extensive vascular network required for corpus luteum integrity and production of progesterone essential for establishing pregnancy. Our findings raise the prospect that disruption of macrophage-endothelial cell interactions underpinning corpus luteum development contributes to infertility in women in whom luteal insufficiency is implicated.

| S-EPMC3726148 | biostudies-literature

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