PGRMC1 Regulates Cellular Senescence via Modulating FOXO1 Expression in Decidualizing Endometrial Stromal Cells

Abstract

The appropriate differentiation of endometrial stromal cells (ESCs) into decidual cells is required for embryo implantation and subsequent placentation into humans. Decidualization is accompanied by the appearance of senescent-like cells. We recently reported the secretory phase-specific downregulation of endometrial progesterone receptor membrane component 1 (PGRMC1) and enhanced decidualization upon PGRMC1 knockdown and inhibition in cultured ESCs. However, it remains unknown whether PGRMC1 is involved in cellular senescence during decidualization. Here, we showed that the small interfering RNA (siRNA)-mediated knockdown of PGRMC1 and the inhibition of PGRMC1 by AG-205 increased the expression of the transcription factor forkhead box protein O1 (FOXO1) and the senescence-associated β-galactosidase activity in cAMP analog- and progesterone-treated ESCs. Furthermore, the knockdown of FOXO1 repressed the decidual senescence induced by siRNA-based PGRMC1 knockdown or AG-205 treatment. Taken together, the decreased PGRMC1 expression in ESCs may accelerate decidualization and cellular senescence via the upregulation of FOXO1 expression for appropriate endometrial remodeling and embryo implantation during the secretory phase.

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

“…Downregulating PGRMC1 after progestin treatment doesn't hamper decidualization, indicating its critical role during the increasing phase and induction. This aligns with observations that PGRMC1 downregulation in the secretory phase promotes decidualization [34]. Overall, PGRMC1 activation by P4 may facilitate the switch from cellular proliferation to decidualization initiation through various biological processes, while the mechanism of how downregulated PGRMC1 promotes decidualization warrants further investigation.…”

“…AG205 was reported to be a speci c inhibitor of PGRMC1 and was broadly used to explore PGRMC1's role in decidualization [34,35]. Recent data, however, question the speci city of AG205 for PGRMC1 [35][36][37].…”

Flip a coin: cell senescence at the maternal–fetal interface

“…Second, interleukin 15 (IL-15) recruits and activates uNK cells at the maternal–fetal interface. The uNK cells remove senescent decidual cells through granule exocytosis, and the interactions between senescent and immune cells ensure embryo invasion and anchoring to the endometrium [47, 48].…”

“…Essentially, cell senescence contributes to the transition of the cycling endometrium into the receptive pregnant decidua [46]. During implantation, EnSCs release SASP factors to create a transient inflammatory environment, which not only contributes to the reprogramming of clonal mesenchymal stem-like cells and induces secondary senescent cells but also recruits uNK cells to limit the process [47]. Altogether, these studies have demonstrated the cooperation between the immune system and senescence at the maternal–fetal interface.…”

Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

“…Clarke et al [445] showed that conditional ablation of pgrmc1 from female reproductive tissues promoted premature reproductive senescence, which arguably could be associated with accelerated aging of those tissues. In a recent study [446], PGRMC1 attenuation in endometrial stromal cells led to the increased expression of the transcription factor forkhead box protein O1 (FOXO1), and the appearance of senescence associated markers which could be reversed by attenuation of FOXO1 levels. Since senescence is an attribute of aging, and PGRMC1 is strongly implicated in senescent biology, these observations promote a strong argument that PGRMC1 is directly involved in aging biology.…”