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Department of Gynecological Endocrinology and Reproductive Medicine, University of Heidelberg, 69115 Heidelberg, Germany, Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany, Division of Endocrinology and Metabolism, Department of Medicine, University of Heidelberg, 69120 Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: roxana.popovici{at}med.uni-heidelberg.de.
Investigating the interaction of human endometrium and trophoblast during implantation is difficult in vitro and impossible in vivo. This study was designed to analyze the effect of trophoblast on endometrial stromal cells during implantation by comprehensive gene profiling. An in vitro co-culture system of endometrial stromal cells with first trimester trophoblast explants was established. Trophoblast and endometrial stromal cells were separated after 24 h. Gene expression of endometrial stromal cells after co-culture was compared with the gene expression of endometrial stromal cells cultured alone by microarray analysis. We confirmed the expression of distinct genes using real-time PCR. Genes up-regulated included those for inflammatory response, immune response and chemotaxis (pentraxin-related gene 3, chemokine ligands, IL-8, IL-1 receptors, IL-18 receptor, IL-15, IL-15 receptor, TNF-
induced protein 6, IL-6 signal transducer), regulators of cell growth (IGFBP-1, IGFBP-2) and signal transduction. Also up-regulated were genes for growth and development, glucose metabolism and lipid metabolism: DKK-1, WISP, IGF2, hydroxysteroid (11-
) dehydrogenase 1, hydroxyprostaglandin dehydrogenase 15, prostaglandin E synthase, prostaglandin F receptor, aldehyde dehydrogenase 1 family, member A3 and phosphatidic acid phosphatase type 2B. Other genes included genes for cell-cell signaling (pre-B-cell colony enhancing factor 1), proteolysis, calcium ion binding, genes for regulation of transcription and others. Down-regulated genes included genes for proteolysis (MMP-11 and mitochondrial intermediate peptidase), genes for cell death (caspase 6; death associated protein kinase 1, histone deacetylase 5), transcription factors (sex determining region Y-box 4, dachshund homolog 1, ets variant gene 1, zinc finger protein 84 and 435) and genes for humoral immune response (CD 24 antigen). Trophoblast has a significant impact on endometrial stromal cell gene expression. Some of the genes regulated by trophoblast in endometrial stromal cells are already known to be regulated by progesterone and show the endocrine function of trophoblast during pregnancy. Others are genes so far unknown to play a role in endometrial-trophoblast interaction and open a wide field of investigation.
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