Melatonin Advances Human Decidualization Through Epithelial-Stromal Crosstalk

Abstract

Background: Embryo implantation and decidualization are essential to the establishment and maintenance of successful pregnancy in both rodents and primates. Receptive endometrium synergism with well-developed blastocyst is prerequisite for successful embryo implantation. Melatonin, which is mainly synthesized by the pineal gland in vertebrates, promotes human blastocyst development and increases pregnancy rate. However, the role and underlying mechanism of melatonin on human endometrial receptivity and decidualization still remains poorly defined. Methods: Trophoblast JEG-3 spheroids were cocultured with endometrial epithelial cells. Real-time PCR, Western blot, siRNA transfection, epithelial-stromal cell coculture system, and assay of Ishikawa cell-conditioned medium were used to explore the effects of melatonin on human endometrial decidualization and the underlying molecular pathways. Findings: In this study, we showed that melatonin induces the expression of the endometrial receptive markers, integrin β3 and HOXA10 in the less-receptive endometrial epithelial cell line AN3 CA and increased the attachment rate of trophoblast JEG-3 spheroids on endometrial epithelial AN3 CA cells. In an epithelial-stromal coculture system, we further proved that melatonin-stimulated IFN-γ secretion from Ishikawa cells promotes in vitro decidualization of stromal cells through regulating progesterone receptor B (PRB). Under in vitro decidualization, IFN-γ significantly increases the levels IGFBP1 and PRL, which is abrogated by suppressing PRB. Under in vitro decidualization of endometrial stromal cells, the expression of the decidualization markers, IGFBP1 and PRL, is significantly stimulated by melatonin treatment. Melatonin obviously increases phosphorylated STAT3 level and decreases p-Akt level. Interpretation: Melatonin may play crucial roles in human endometrial receptivity and decidualization. The dialogue between endometrial epithelial and stromal cell mediated by melatonin should be beneficial for decidual process. Funding: National Key R&D Program of China (2018YFC1004403) and National Natural Science Foundation of China (31671563, 31871511). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: All human procedures were approved by the Institutional Committee on the Use of Human Subjects in Medical Research of Southern Medical University with written consent.