<scp>NR5A1</scp> Deficiency Leads to Decidualization Dysregulation of Stromal Cells and Recurrent Spontaneous Abortion During Early Pregnancy

The differentiation of endometrial stromal cells (ESCs) into decidual stromal cells (DSCs), that is, endometrial decidualization, orchestrates the receptive environment for early embryo development, and defects in decidualization lead to unexplained recurrent spontaneous abortion (URSA). Nuclear receptor subfamily 5 group A member 1 (NR5A1) is involved in endometrial decidualization during early pregnancy, but its role is limitedly understood. Here, we elucidated the association between low expression of NR5A1 and decidualization dysregulation and URSA during early pregnancy, and then elucidated mechanisms of NR5A1 regulating decidualization. In the endometrium, the expression level of NR5A1 in secretory-phase ESCs of URSA patients was lower than that of controls. During early pregnancy, the expression level of NR5A1 in DSCs from URSA patients, and that in decidua of recurrent spontaneous abortion (RSA) mice, were decreased in comparison with controls, respectively. NR5A1 knockdown impaired in vitro decidualization of ESCs by inhibiting the IGFBP1 up-regulation and F-actin formation. In DSCs of early pregnancy mice, NR5A1 was maintained at a higher level from pregnant Day 4. Downknocking NR5A1 by intrauterine injection of RNAi-Nr5a1 lentiviruses in mice increased the embryonic resorption and impaired decidualization by down-regulating the expression of Dtprp and IGFBP1. Dual-luciferase reporter and ChIP-qPCR assays revealed that NR5A1 bound to the IGFBP1 promoter and then activated its transcription. In mice with downknocked NR5A1 in the uterus, restoring IGFBP1 expression by injecting Igfbp1-overexpression lentiviruses rescued embryonic resorption. These data indicated that NR5A1 was indispensable for endometrial decidualization and that the NR5A1 reduction in secretory endometrium and early decidua may lead to URSA.