Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators

Department of Obstetrics and Gynecology, Stanford University, Palo Alto, California, United States
Biology of Reproduction (Impact Factor: 3.32). 02/2007; 76(1):102-17. DOI: 10.1095/biolreprod.106.054791
Source: PubMed


During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important for successful embryonic implantation, including establishing the placental vasculature, anchoring the placenta to the uterine wall, and promoting the immunoacceptance of the fetal allograph. To our knowledge, global crosstalk between the trophoblast and the decidua has not been elucidated to date, and the present study used a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and further treated with conditioned media from human trophoblasts (TCM) or, as a control, with control conditioned media (CCM) from nondecidualized stromal cells for 0, 3, and 12 h. Total RNA was isolated and processed for analysis on whole-genome, high-density oligonucleotide arrays containing 54,600 genes. We found that 1374 genes were significantly upregulated and that 3443 genes were significantly downregulated after 12 h of coincubation of stromal cells with TCM, compared to CCM. Among the most upregulated genes were the chemokines CXCL1 (GRO1) and IL8,CXCR4, and other genes involved in the immune response (CCL8 [SCYA8], pentraxin 3 (PTX3), IL6, and interferon-regulated and -related genes) as well as TNFAIP6 (tumor necrosis factor alpha-induced protein 6) and metalloproteinases (MMP1, MMP10, and MMP14). Among the downregulated genes were growth factors, e.g., IGF1, FGF1, TGFB1, and angiopoietin-1, and genes involved in Wnt signaling (WNT4 and FZD). Real-time RT-PCR and ELISAs, as well as immunohistochemical analysis of human placental bed specimens, confirmed these data for representative genes of both up- and downregulated groups. The data demonstrate a significant induction of proinflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune environment of the decidua to facilitate the process of implantation and ensure an enriched cytokine/chemokine environment while limiting the mitotic activity of the stromal cells during the invasive phase of implantation.

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Available from: Jan Steffen Kruessel, Jan 11, 2014
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    • "Deficiency in Wnt6 resulted in impaired stromal cell proliferation with minimal effects on differentiation (Wang et al. 2013). In an in vitro study, it was reported that Wnt4 and Fz2 expression is downregulated in primary decidualised endometrial stromal cells in the presence of trophoblast conditioned media, suggesting a paracrine mode of regulation of decidualisation by trophoblasts through Wnt signalling (Hess et al. 2007). The opposite pattern of Wnt4 expression found in that study may be due to species-specific differences between mice and humans, or noted endocrine influences in the in vivo studies (Fig. 2). "
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    ABSTRACT: The integration of a complex network of signalling molecules promotes implantation of the blastocyst and development of the placenta. These processes are crucial for a successful pregnancy and fetal growth and development. The signalling network involves both cell-cell and cell-extracellular matrix communication. The family of secreted glycoprotein ligands, the Wnts, plays a major role in regulating a wide range of biological processes, including embryonic development, cell fate, proliferation, migration, stem cell maintenance, tumour suppression, oncogenesis and tissue homeostasis. Recent studies have provided evidence that Wnt signalling pathways play an important role in reproductive tissues and in early pregnancy events. The focus of this review is to summarise our present knowledge of expression, regulation and function of the Wnt signalling pathways in early pregnancy events of human and other model systems, and its association with pathological conditions. Despite our recent progress, much remains to be learned about Wnt signalling in human reproduction. The advancement of knowledge in this area has applications in the reduction of infertility and the incidence and morbidity of gestational diseases.
    Reproduction Fertility and Development 09/2014; DOI:10.1071/RD14079 · 2.40 Impact Factor
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    • "Costello et al. demonstrated that ectopic expression of NOD2 in a first trimester trophoblast cell line, H8, produced higher levels of cytokines than with vehicle treatment alone [22], suggesting that intracellular NOD2 expression levels affect baseline production of cytokines. NOD2 expression may be crucial for the balance of chemokine and cytokine signaling at the maternal-fetal interface that is essential during implantation and placentation [39]–[42]. "
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    ABSTRACT: NOD2, one of the cytosolic proteins that contain a nuclear oligomerization domain (NOD), is a pattern recognition receptor (PRR) involved in innate immune responses to intracellular pathogens. Little is known, however, about the effect of NOD2 expression on the maternal-fetal relationship. Our aim was to elucidate the functions of NOD2 in normal decidual stromal cells (DSCs) from the first trimester. Tissues and DSCs were isolated from 26 patients with normal pregnancies that required abortion. The expression of NOD2 in deciduas/decidual stromal cells (DSCs) was examined by real-time PCR, immunohistochemistry, and In-cell western. DSCs containing NOD2 were stimulated by its ligand, muramyl dipeptide (MDP). The secretion of various cytokines and chemokines were measured by ELISA and the apoptotic rate was determined by flow cytometry. Treatment with MDP significantly elevated the expression of both NOD2 mRNA and protein levels in DSCs. In addition, MDP activation of NOD2 significantly increased IL-1β and MCP-1 cytokine expression in a dose dependent manner but had no effect on IL-12 expression. IL-1β and TNF-α also significantly increased the expression of NOD2 in DSCs, suggesting a positive feedback loop mechanism. Moreover, MDP stimulation augmented DSC apoptosis. In summary, the results suggest that NOD2 expression in DSCs plays an important role in protecting the embryo and preventing infection in the maternal-fetal interface.
    PLoS ONE 06/2014; 9(6):e99612. DOI:10.1371/journal.pone.0099612 · 3.23 Impact Factor
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    • "The downregulated genes were growth factors, such as IGF1, FGF1, and the genes involved in Wnt signaling. Paracrine interactions between EVT and the maternal decidua are therefore essential for successful embryonic implantation, which occurs in an enriched cytokine/chemokine environment where stromal cells' mitotic activity is limited in the invasive implantation phase [69]. A prior in vitro study also revealed that the most overexpressed genes by endometrial stromal cells during implantation, due to the effect of the trophoblast, were those involved in inflammatory response, immune response and chemotaxis (PTX3, IL8, IL1 receptors, IL18 receptor, and TNFAIP6), cell growth regulators (IGF-binding proteins 1 and 2), and signal transduction. "
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    ABSTRACT: Maternofetal immune tolerance is essential to maintain pregnancy. The maternal immunological tolerance to the semiallogeneic fetus becomes greater in egg donation pregnancies with unrelated donors as the complete fetal genome is allogeneic to the mother. Instead of being rejected, the allogeneic fetus is tolerated by the pregnant woman in egg donation pregnancies. It has been reported that maternal morbidity during egg donation pregnancies is higher as compared with spontaneous or in vitro fertilization pregnancies. Particularly, egg donation pregnancies are associated with a higher incidence of pregnancy-induced hypertension and placental pathology. Preeclampsia, a pregnancy-specific disease characterized by the development of both hypertension and proteinuria, remains the leading cause of maternal and perinatal mortality and morbidity. The aim of this review is to characterize and relate the maternofetal immunological tolerance phenomenon during pregnancies with a semiallogenic fetus, which are the spontaneously conceived pregnancies and in vitro fertilization pregnancies, and those with an allogeneic fetus or egg donation pregnancies. Maternofetal immune tolerance in uncomplicated pregnancies and pathological pregnancies, such as those with preeclampsia, has also been assessed. Moreover, whether an inadequate maternal immunological response to the allogenic fetus could lead to a higher prevalence of preeclampsia in egg donation pregnancies has been addressed.
    Research Journal of Immunology 06/2014; 2014:210241. DOI:10.1155/2014/210241
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