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Department of Obstetrics, Gynecology, and Reproductive Sciences,4 University of California, San Francisco, California 94143-0132
Department of Obstetrics and Gynecology,5 Heinrich-Heine University, 40225 Duesseldorf, Germany
Departments of Medicine6 and Obstetrics and Gynecology,7 Stanford University, Stanford, California 94305
Department of Stomatology,8 University of California, San Francisco, California 94143-0512
Department of Obstetrics and Gynecology,9 University of Illinois, Chicago, Illinois 60612-7313
Department of Pathology,10 John Stroger Jr. Hospital of Cook County, Chicago, Illinois 60612-3714
ABSTRACT
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.
decidua, gene regulation, immunology, implantation, trophoblast
3These authors contributed equally to this work.
1Supported by the German Research Foundation (Deutsche Forschungsgemeinschaft HE 3544/1 to A.P.H.) and by the NIH Cooperative Program in Trophoblast-Maternal Tissue Interactions U-01 HD-42280 (to A.T.F.), U-01 HD-42283 (to S.J.F.), and U-01 HD-42298 to (L.C.G.). All gene expression arrays and raw .CEL files have been deposited with the National Center for Biotechnology Information gene expression and hybridization array data repository (GEO, available at http://www.ncbi.nlm.nih.gov/geo/), GEO accession number GSE5809.
Correspondence: 2 Linda C. Giudice, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, Parnassus Ave., M1495, Box 0132, San Francisco, CA 94143-0132. FAX: 415 476 1811; e-mail: giudice{at}obgyn.ucsf.edu
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