Decidual Invasion Research Articles

Redeployment of Placental Gene Programming: Can Invasive Placentation Molecular Switches Complement the Hallmarks of Cancer?

Placentation arose in mammalian evolution some 150-200 M years ago and integrates in a rather ingenious manner a large number of previously evolved multicellular regulatory pathways which include: angiogenesis, inflammatory cytokines and interleukins, HLA expression, immune peptides, immune regulatory receptors (for NK decidual cells, T and B cells, including Tregs, macrophages, antigen-presenting cells ), endothelial cells and fibroblasts, immune checkpoints (including PD-L1), many paracrine or endocrine hormones and growth factors, tissue enzymes, extracellular vesicles, several different mechanisms for epithelial-mesenchymal transitions, several hypoxia adaptations, morphogenetic changes, and others. Speculating from real genomics and epigenetic data from a single clinical case of a pregnant young woman with breast cancer, it has been recently proposed that mammalian cancer cells do not have to invent “de novo” immune escape mechanisms, including so-called “immune editing”, but to redeploy–probably by epigenetic mechanisms–intrinsic or encrypted gene programmes physiologically used by the process of invasive placentation in mammals. Most of these programmes were not evolved specifically for the placenta–but there were probably some exceptions, such as those still poorly understood key pathways related to foeto-maternal tolerance or perhaps trophoblast differentiation and decidual invasion. In my opinion, invasive placentation molecular switches can complement the hallmarks of cancer, by re-using “placental gene programming” to the competitive advantage of cancer cells.

O-046 Implantation and beyond, the endometrial perspective

Abstract text Early pregnancy failures are spread throughout the first few weeks, suggesting that impairment of normal biological processes can occur at sequential stages: epithelial attachment and breaching, early stromal and then decidual invasion, glandular and vascular invasion. Biopsy-based transcriptomics and proteomics have failed to demonstrate a reproducible or interpretable molecular signature for endometrial receptivity, but single cell RNAseq suggests a step change in the epithelial transcriptome in the mid secretory phase, consistent with the appearance of new cell phenotype(s). Previously unseen heterogeneity in both epithelial and stromal cell populations has become evident, but gene signatures have not yet achieved a level of resolution that allows insights clear enough to decode the biology of the receptive state. However, methodology for propagating and recombining endometrial cell populations into 3D engineered tissue models has advanced, so that new mechanistic questions can be asked. Initial acquisition of receptivity to implantation is followed by the development of a supportive environment for embryos that possess the capacity to progress, with maternal cell populations (epithelial, stromal, immune and vascular) acting cooperatively within a remodelling extracellular matrix (ECM). A balance must be achieved in the ECM between breakdown, with opening of hydrated spaces to allow expansion of the embryonic sac while maintaining a substrate for stable physical attachment to allow invasion by extravillous trophoblast. The extent and nature of cellular trafficking to and from the uterus is important before and during early pregnancy. There is evidence that regulation of a resident senescent cell subpopulation by uterine NK cells occurs in concert with ECM remodelling to achieve a functionally supportive environment in the early first trimester. Access of bone marrow-derived cells to vessel walls is regulated by placental-endothelial signalling to initiate remodelling for the increased blood flow to the conceptus that is required in later pregnancy. Thus ‘receptivity’ and ‘supportiveness’ require normal cell proportions and functional phenotypes in multiple endometrial cell populations and their physical environment in order to allow a well-calibrated sequential developmental response in the conceptus.

Decidual Hemostasis, Inflammation, and Angiogenesis in Pre-Eclampsia

Invasion of the decidua by extravillous trophoblasts (EVTs) is accompanied by thrombin generation from decidual cell (DC)-expressed tissue factor (TF). This TF protects against hemorrhage as EVTs breach capillaries and subsequently invade and remodel spiral arteries and arterioles. Pre-eclampsia (P-EC) is the world's leading cause of fetal and maternal morbidity and mortality. It is associated with decidual hemorrhage and maternal thrombophilias, which form excess thrombin from DCs, and with maternal infections and other inflammatory conditions that are associated with excess expression of the proinflammatory cytokines interleukin (IL)-1 β and tumor necrosis factor (TNF) α. In human first-trimester leukocyte-free DCs, (1) thrombin enhances expression of soluble fms-like tyrosine kinase-1 (sFlt-1), a potent inhibitor of angiogenesis; (2) thrombin, IL-1β and TNF-α increase monocyte-recruiting chemokine expression leading to a macrophage excess in the pre-eclamptic decidua. The pathogenesis of P-EC likely stems from shallow EVT invasion leading to impaired decidual vascular remodeling. The resulting reduced uteroplacental blood flow is associated with a hypoxic placenta, which appears to secrete excess sFlt-1 into the maternal plasma. A regulatory role for DCs in vascular remodeling is indicated because impaired decidual vascular remodeling could stem from an aberrant local antiangiogenic milieu elicited by excess sFlt-1 and/or macrophage-inhibited EVT decidual invasion.

Localization of Cathepsins D and B at the Maternal-Fetal Interface and the Invasiveness of the Trophoblast during the Postimplantation Period in the Mouse

A survey of existing data suggests that trophoblast cells produce factors involved in extracellular matrix degradation. In this study, we correlated the expression of cathepsins D and B in the murine ectoplacental cone with the ultrastructural progress of decidual invasion by trophoblast cells. Both proteases were immunolocalized at implantation sites in lysosome-endosome-like compartments of trophoblast giant cells. Cathepsin D, but not cathepsin B, was also detected ultrastructurally in extracellular compartments surrounded by processes of the invading trophoblast containing extracellular matrix components and endometrial cell debris. The expression of cathepsins D and B by trophoblast cells was confirmed by RT-PCR in ectoplacental cones isolated from implantation chambers at gestation day 7.5. Our data addressed a positive relationship between the expression and presence of cathepsin D at the extracellular compartment of the maternal-fetal interface and the invasiveness of the trophoblast during the postimplantation period, suggesting a participation of invading trophoblast cells in the cathepsin D release. Such findings indicate that mouse trophoblast cells might exhibit a proteolytic ability to partake in the decidual invasion process at the maternal-fetal interface.

TGF-β superfamily expression and actions in the endometrium and placenta

Transforming growth factor beta (TGFbeta) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFbeta superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFbetas and activin beta subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFbetas, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFbeta superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFbeta and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFbeta superfamily members participate in modulating the extent of decidual invasion. Activins and TGFbetas have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down's syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

Le placenta humain et ses pathologies : l’oxygène en question

At the time of placentation, the conceptus surrounds itself with a trophoblastic layer where the villous tree develops and the uteroplacental circulation takes place. Analysis of the modalities of maternal blood entrance demonstrated a physiological hypoxia ending with the first trimester of pregnancy. Moreover, cultures of first trimester villous explants have shown the role of oxygen in extravillous cytotrophoblast proliferation, decidual invasion and spiral artery remodeling. Oxygen appears to be a key factor controlling the mechanism of placentation by regulating the transcription of several genes, such as VEGF (vascular endothelial growth factor), leptin, etc. These genes are turned on or off as a function of oxygen partial pressure via an oxygen sensor. Oxygen is now considered to be implicated in the development of several pathologies of pregnancy. It is involved at different steps in the cascade of events leading to preeclampsia. Positive correlations have been observed between oxygen partial pressure and abnormal development of the villous tree in intrauterine growth retardation, and in maternal anemia or pregnancy in altitude.

Gestational regulation of granulocyte-colony stimulating factor receptor expression in the human placenta.

A number of cytokines and their receptors are abundantly expressed at the materno-fetal interface and are thought to have a function in the regulation of placentation. Granulocyte-colony stimulating factor (G-CSF) is expressed by stromal cells in both placental tissue and maternal decidua throughout placentation. In this study, we examined the expression of placental G-CSF receptor (G-CSFR) mRNA and protein throughout gestation by ribonuclease protection assays, Western blotting, and immunohistochemistry. The major placental form of G-CSFR mRNA, corresponding to a membrane-bound form of the protein, was present in first-trimester placental tissues; levels decreased in second- and were highest in third-trimester placental tissues. Two placental G-CSFR molecules, 120 kDa and 150 kDa, were detected in first- and third-, but not second-, trimester tissues. The level of the 150-kDa G-CSFR was greater in the third- than in first-trimester samples. These differences were irrespective of whether or not the patients had received prostaglandin E1 analogues, prostaglandin E1 analogues and oxytocin, oxytocin alone, or mifepristone before labor. We demonstrated by immunohistochemistry that interstitial cytotrophoblast in first- and second-trimester decidual tissue and cytotrophoblast in term fetal membranes express G-CSFR. These data demonstrate that the expression of specific forms of placental G-CSFR is strictly cell type- and developmental stage-specific, and they suggest that G-CSFR may be important in decidual invasion of cytotrophoblast and in trophoblast function during placentation.

The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome.

The antiphospholipid (aPL) antibody syndrome is characterized by severe pregnancy complications, the cause of which remains unknown. We hypothesized that the placental trophoblast is a target for aPLs. The effects of monoclonal aPLs on trophoblast function, including the invasion of JAR into matrigel-coated filters and the effects of annexin V expression on BeWo, were investigated using choriocarcinoma models. aPLs against phosphatidylserine (PS) significantly (P < 0.001) decreased the migration of JAR across the membrane. In the annexin V studies, undifferentiated BeWo did not express surface annexin V. After differentiation, BeWo expressed surface annexin V, which was removed in the presence of aPLs, resulting in increased binding of prothrombin. PS is expressed on the trophoblast surface during differentiation and invasion of extracellular matrix. Our data suggest that aPLs against PS can directly affect trophoblast function by limiting the depth of decidual invasion and by concurrently creating a procoagulant surface on trophoblast exposed to the maternal circulation.