| Summary: | 碩士 === 國立陽明大學 === 解剖學及細胞生物學研究所 === 106 === Embryo implantation is a complex process and regulated by diverse endometrial factors, including cytokines, growth factors, and their receptors. Successful implantation depends on an adequately primed-endometrium, a healthy blastocyst and meticulous cross-communication. During the mid-luteal phase, the endometrium becomes receptive and ready to accept the embryo for implantation, and this period is called the implantation window. Furthermore, the embryo biological functions including apposition, adhesion, and invasion also play a critical role of implantation. Poor trophoblast cell migration and invasion may cause miscarriage and pre-eclampsia. In vitro fertilization (IVF) is a common assisted reproductive technique (ART) for treatment with infertility. Previous studies have shown that the endometrial maturation of fresh IVF cycle may be more advanced than the natural cycle (NC), and the endometrial receptivity is compromised after ovarian stimulation for IVF.
In this study, we wanted to determine the difference of endometrial stromal cell secretion of cytokines during implantation window between natural and stimulated cycles, and understand the effects of secretion from human endometrial stromal cell on human trophoblast cells. First, we found that conditioned medium of human endometrial stromal cells could decrease human BeWo tropholast cell proliferation at high concentrations, but it could dose-dependently enhance cell migration. The high expression of interleukin- (IL)- 6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2) were detected by human cytokine array in endometrial secretion of natural cycle and IVF stimulated cycle, and the expression of IL-6, IL-8 and CCL2 in IVF stimulated cycle was higher than natural cycle. Next, we focused on the effects of these three cytokines on the proliferation and migration of human BeWo trophoblast cells. The results showed that IL-6 and IL-8 had no effect on the cell proliferation, whereas they could enhance the capacity of cell migration. CCL2 could decrease cell proliferation at high concentrations, but had no effect on cell migration. In the intracellular signalling pathways, phosphorylation of STAT3 was increased upon the treatment of IL-6. In addition, inhibition of STAT3 phosphorylation by STAT3 inhibitor (cryptotanshinon) resulted in suppression of IL-6-mediated migration. Therefore, the IL-6-enhanced trophoblast cell migration was mediated by phosphorylation of STAT3. On the other hand, Akt activation was involved in IL-8-promoted trophoblast cell migration. These results suggest that the endometrial secretion of IL-6 and IL-8 could promote the trophoblast migration and the signaling cascade was regulated by the STAT3 and Akt pathways, respectively. In the future, we would further investigate whether the endometrial stromal cell-conditioned medium and the related cytokines can be applied in assisted reproductive technology to increase implantation rates.
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