Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.

/pdf/cyclic-decidualization-of-the-human-endometrium-in-1iwdpp6xfx.pdf

Cyclic decidualization of the human endometrium in reproductive health and failure.

Derivation of Human Trophoblast Stem Cells

Preeclampsia is a leading cause of pregnancy-related morbidity and mortality in the United States. In the past 30 years, a large amount of research has been performed to investigate the pathogenesis and pathophysiology of preeclampsia, ways to treat preeclampsia, markers that can be used to predict

A critical review of early-onset and late-onset preeclampsia.

Abnormal placentation is considered as an underlying cause of various pregnancy complications such as miscarriage, preeclampsia and intrauterine growth restriction, the latter increasing the risk for the development of severe disorders in later life such as cardiovascular disease and type 2 diabetes. Despite their importance, the molecular mechanisms governing human placental formation and trophoblast cell lineage specification and differentiation have been poorly unravelled, mostly due to the lack of appropriate cellular model systems. However, over the past few years major progress has been made by establishing self-renewing human trophoblast stem cells and 3-dimensional organoids from human blastocysts and early placental tissues opening the path for detailed molecular investigations. Herein, we summarize the present knowledge about human placental development, its stem cells, progenitors and differentiated cell types in the trophoblast epithelium and the villous core. Anatomy of the early placenta, current model systems, and critical key regulatory factors and signalling cascades governing placentation will be elucidated. In this context, we will discuss the role of the developmental pathways Wingless and Notch, controlling trophoblast stemness/differentiation and formation of invasive trophoblast progenitors, respectively.

/pdf/human-placenta-and-trophoblast-development-key-molecular-44s7t75r34.pdf

Human placenta and trophoblast development: key molecular mechanisms and model systems.

Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

/pdf/uterine-nk-cells-active-regulators-at-the-maternal-fetal-2a913qdunl.pdf

Uterine NK cells: active regulators at the maternal-fetal interface

Fusion of the trophoblast-derived choriocarcinoma cell line BeWo can be triggered by forskolin. BeWo cells are regularly used as a cell culture model to mimic in vivo syncytialisation of placental villous trophoblast. The β subunit of human chorionic gonadotropin (CGB), placental alkaline phosphatase as well as placental protein 13 (PP13, LGALS13) are exclusively expressed in the syncytiotrophoblast of the human placenta, and CGB is commonly used as a marker of syncytial differentiation. Here we tested the hypothesis that syncytial fusion precedes CGB and LGALS13 expression in trophoblast-derived BeWo cells. BeWo cells were cultured for 48 h in the presence or absence of forskolin and varying concentrations of H-89, a protein kinase A inhibitor that interferes with the forskolin-mediated pathway of syncytial fusion. LGALS13 and CGB expression were quantified by DELFIA and real-time PCR. Cell fusion was determined by morphological analysis and cell counting after immunofluorescence staining. In forskolin-stimulated BeWo cells that were hindered to fuse by treatment with H-89, levels of CGB protein expression were not altered, while LGALS13 protein and mRNA expression decreased significantly to control levels without forskolin. The LGALS13 protein expression data coincided with a significant decrease in syncytial fusion, while CGB protein expression was unaffected by rates of cell fusion and proliferation. We postulate that CGB protein expression is not necessarily linked to syncytial fusion, and thus CGB should be used with great caution as a marker of BeWo cell fusion.

/pdf/the-choriocarcinoma-cell-line-bewo-syncytial-fusion-and-1m42i46vmq.pdf

The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins.

Factors involved in regulating trophoblast fusion: potential role in the development of preeclampsia.

BACKGROUND: Routes of trophoblast invasion seem to be clear, whereas specific invasive pathways need further elucidation. Extravillous trophoblasts (EVTs) transform spiral arteries to guarantee appropriate blood flow to the placenta in the second trimester. Embryo nutrition during the first trimester is thought to be histiotrophic, whereas proof that EVTs also invade uterine glands is lacking. We developed novel three-dimensional confrontation co-culture models to elucidate invasion of EVTs into uterine glands. METHODS: First trimester decidua parietalis and placental villous explants were directly confronted and co-cultured for 72 h, or confronted indirectly after 72 h pre-culture for re-epithelialization of decidua pieces. Cryosections were stained by immunohistochemistry or immunofluorescent/immunohistochemical double labelling and compared with first trimester placentation sites in situ. RESULTS: EVTs deeply invaded decidual tissues in direct confrontation assays and were found between the decidual epithelial cells and epithelial basement membrane. EVTs were also detected in the decidual stroma in direct proximity to glands, sometimes even replacing glandular epithelial cells. Similar observations were made in sections from the first trimester decidua/placental bed. In the invaded parts of sections of decidua basalis, 55% +/- 7% (mean +/- SEM; n = 10, range 6-11 weeks) of glandular cross sections were associated with or infiltrated by EVTs. CONCLUSIONS: Using novel confrontation co-culture assays, a potential new route of EVT invasion was detected. EVTs appear to break through the basement membrane of uterine glands to open their lumen towards the intervillous space. These data support the hypothesis of histiotrophic nutrition of the embryo prior to onset of maternal blood flow within the placenta.

Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models

Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions

Until recently, trophoblast invasion during human placentation was characterized by and restricted to invasion into uterine connective tissues and the uterine spiral arteries The latter was explained to connect the arteries to the intervillous space of the placenta and to guarantee the blood supply of the mother to the placenta Today, this picture has dramatically changed Invasion of endoglandular trophoblast into uterine glands, already starting at the time of implantation, enables histiotrophic nutrition of the embryo prior to perfusion of the placenta with maternal blood This is followed by invasion of endovenous trophoblasts into uterine veins to guarantee the drainage of fluids from the placenta back into the maternal circulation throughout pregnancy In addition, invasion of endolymphatic trophoblasts into the lymph vessels of the uterus has been described Only then, invasion of endoarterial trophoblasts into spiral arteries takes place, enabling hemotrophic nutrition of the fetus starting with the second trimester of pregnancy This new knowledge paves the way to identify changes that may occur in pathological pregnancies, from tubal pregnancies to recurrent spontaneous abortions

/pdf/human-trophoblast-invasion-new-and-unexpected-routes-and-1l42uveg4u.pdf

Gerit Moser

Papers

The choriocarcinoma cell line BeWo: syncytial fusion and expression of syncytium-specific proteins.

Factors involved in regulating trophoblast fusion: potential role in the development of preeclampsia.

Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models

Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions

Human trophoblast invasion: new and unexpected routes and functions