Progesterone-induced Progesterone Receptor Membrane Component 1 Rise-to- Decline Changes are Essential for Decidualization

Abstract

Abstract Background Decidualization of endometrial cells is the prerequisite for embryo implantation and subsequent placenta formation and is induced by rising progesterone levels following ovulation. One of the hormone receptors contributing to endometrial homeostasis is Progesterone Receptor Membrane Component 1 (PGRMC1), a non-classical membrane-bound progesterone receptor with yet unclear function. In this study, we aimed to investigate how PGRMC1 contributes to human decidualization. Methods To gain insight into PGRMC1-implication in infertility-related diseases, we analyzed its expression profile in RNA-sequencing datasets of endometrial biopsies. To further explore the function of PGRMC1 in human decidualization, we implemented an inducible decidualization system, which is achieved by culturing two human endometrial stromal cell lines in decidualization-inducing medium containing medroxyprogesterone acetate and 8-Br-cAMP. In our system, we measured PGRMC1 expression during hormone induction as well as decidualization status upon PGRMC1 knockdown at different time points. We further conferred proximity ligation assay to identify PGRMC1 interaction partners. Results PGRMC1 expression was altered in patients with infertility-related diseases and impaired decidualization, being significantly downregulated in most datasets. In in vitro experiments, we observed that PGRMC1 expression follows a rise-to-decline pattern, in which its expression level initially increased during the first 6 days after induction (PGRMC1 increasing phase) and decreased in the following days (PGRMC1 decreasing phase). Knockdown of PGRMC1 expression before the induction led to a failed decidualization, while its knockdown after induction did not inhibit decidualization, suggesting that the progestin-induced ‘PGRMC1 increasing phase’ is essential for normal decidualization. Furthermore, we found that the interactions of PHB1 and PHB2 with PGRMC1 were induced upon progestin treatment. Knocking down either PHB individually or both slowed down the decidualization process compared to the control, suggesting that PGRMC1 cooperates with PHBs to regulate the decidualization. Conclusions According to our findings, PGRMC1 expression followed a progestin-induced rise-to-decline expression pattern during human endometrial decidualization process; and the correct execution of this expression program was crucial for successful decidualization. Thereby, the results of our in vitro model explained how PGRMC1 dysregulation in patients with impaired decidualization contributes to the manifestation of their disease.