Resveratrol enhances decidualization of human endometrial stromal cells

Abstract

The differentiation of endometrial stromal cells (ESC), named decidualization, is essential to regulate trophoblast invasion and to support pregnancy establishment and progression. Decidualization follows ESC proliferation and it has been described that cell cycle arrest contributes to a proper decidualization. Interestingly, resveratrol, a natural compound derived from grapes with antioxidant properties, has been widely studied in relation to endometrial health. However, little is known about the effect of resveratrol supplementation during decidualization. Therefore, in this study we evaluate the effect of resveratrol supplementation during decidualization. We used primary and immortalized human ESC and we decidualized them in vitro with a decidualization cocktail containing medroxyprogesterone acetate, estradiol and 8-Bromo-cyclic AMP. Pre-decidualized cells were further treated with the decidualization cocktail supplemented with resveratrol. Our results show that resveratrol supplementation increased, in a dose-dependent manner, the expression levels of prolactin and IGFBP1 (RT-PCR and ELISA), indicating an enhanced in vitro decidualization of human ESC. This enhanced decidualization was accompanied by a decrease in cell proliferation (crystal violet and CellTiter proliferation assay) and by changes in the mRNA levels of key cell cycle regulators (RT-PCR). Furthermore, resveratrol supplementation seemed to enhance decidualization by reinforcing the effect of the decidualization cocktail. We believe that resveratrol could to be an effective supplementation to reinforce hormone action during human ESC decidualization and that further insights into resveratrol action and its interaction with estradiol and progesterone signaling pathways could facilitate the identification of new therapeutic strategies for the improvement of women’s health.

Resveratrol and Reproductive Health

“…Beneficial effects of RSV on ovaries include activation of SIRT1 molecules. This activation leads to anti-oxidative effects, which protect oocytes from senescence-dependent damage [18]. Also, RSV-induced SIRT1 upregulation increases levels of LH (but not FSH) receptors and steroidogenic enzymes (aromatase) in the model of rat ovaries [19].…”

“…In fact, during embryo transfer, RSV may act adversely on the decidualization process in spite of good competency of the transferred embryos [24]. Additionally, RSV activates calcium dependent SIRT1-modulated attachment of an embryo to the endometrium, and, due to its antiproliferative and antiapoptotic effects, prevents formation of an ectopic endometrium [18]. In a sheep animal model, nuclear maturation rate or intracellular oxidative status in cloned embryos have not been significantly improved by 0.5 µM concentrations of RSV [25].…”

“…Conversely, since the requirements for the successful pregnancy consist of decidualization (hence, trophoblast invasion) and activation of the local inflammatory response, due to other properties, RSV may suppress embryo implantation [18]. In fact, hormonal changes and consequent morphological events of the endometrium (decidualization of HESC), trophoblast invasion, cell differentiation and apoptosis) denoting the development of normal pregnancy [20] can be highly detrimented by RSV supplementation, and lead to an implantation failure and pregnancy loss, mostly due to its antiapoptotic and antisenescence activity [18]. These properties of RSV represent the main disadvantage for the treatment of infertility, since normal decidualization entails apoptosis/senescence activity and consecutive differentiation of the cells.…”

“…Additionally, retinoic acid (RA) activates signal pathways involving several regulatory proteins: cellular retinoic acid-binding protein 2 (CRABP2) and fatty acids binding protein 5 (FABP5,) which promote genes to cause cellcycle arrest and peroxisome-proliferating activated receptor (PPAR), which promotes cell differentiation [28]. Normally, decidualization first increases and then decreases RA-PPAR signaling, while decidual cell secrete proapoptotic factors (p16 and p53) [18,28]. RSV leads to downregulation of CRABP2-RAR signaling, which suppresses the expression of p53 and causes implantation failure, along with the inhibition of prolactin (PRL) induction (a widely used decidual marker gene) and IGFBP1 (insulin-like growth factor-binding protein-1) [29].…”

Autophagy as a Therapeutic Target of Natural Products Enhancing Embryo Implantation

“…Four compounds, berberine, emodin, paeoniflorin, and γ-tocotrienol, increased implantation rates by increasing endometrial receptivity or decidualization [103,116,120,131,132]. In contrast, resveratrol has been shown to have dual effects as an agonist and antagonist [133,134]. Kuroda et al [135] compared these reports and concluded that the timing of drug treatment is important in modulating the decidual response.…”