NR4A1 Affects Endometrial Receptivity by Participating in Mesenchymal-Epithelial Transition of Endometrial Stromal Cells.

Decidualization is a substantive differentiation process experienced by endometrium to prepare for pregnancy. During this process, the endometrial stromal cells are transformed to endometrial epithelial cells. The receptivity of endometrium is necessary for the decidualization and successful implantation of endometrium, while the main hormones coordinating this process are estrogen and progesterone (P). In our study, the immunofluorescence, qPCR, and western blot experiments were conducted on different types of clinical endometrial tissue samples. The experimental results show that in the endometrium of normal subjects during the luteal phase, the protein level and serum P4 level of the orphan nuclear receptor NR4A1 messenger RNA were all significantly higher than those of patients with endometriosis or primary infertility, and the two levels presented positive correlation. Through decidualization induction of the human endometrial stromal cells (hESCs) cultured in vitro and additional P treatment, the results of chromatin immunoprecipitation and other experiments show that the P treatment could upregulate the expression of NR4A1 in hESCs, and this process was mediated under the direct effect of progesterone receptor (PR) and NR4A1. When the NR4A1 in hESCs was silenced, the promotion of hESC proliferation by P was inhibited. P and overexpressed NR4A1 increased the expression of epithelial cell marker in decidual hESCs, and qPCR showed that NR4A1's response to P was earlier than that of the epithelial cell marker. The results of spheroid adhesion assay show that the silent NR4A1 had reduced the adhesion of decidual hESCs induced in vitro to embryo. To sum it up, NR4A1 participated in the decidualization process by responding to the P regulation via and by promoting the hESCs' mesenchymal-epithelial transition, so as to further influence the receptivity of endometrium.