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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    • "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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