Human Endometrial Stromal Cell Differentiation is Stimulated by PPARβ/δ Activation: New Targets for Infertility?

CONTEXT Implantation is a reproductive bottleneck in women, regulated by fluctuations in ovarian steroid hormone concentrations. However, other nuclear receptor ligands are modifiers of endometrial differentiation leading to successful pregnancy. In the current study we analyzed the effects of PPARβ/δ activation on established cellular biomarkers of human endometrial differentiation (decidualization). OBJECTIVE To test the effects of PPARβ/δ ligation on human endometrial cell differentiation. DESIGN Isolated primary human endometrial stromal cells (ESC) were treated with synthetic (GW0742) or natural (all trans-retinoic acid, RA) ligands of PPARβ/δ, and also with receptor antagonists (GSK0660, PT-S58 and ST247) in the absence or presence of decidualizing hormones (10 nM estradiol, 10 nM progesterone and 0.5 mM dibutyryl cAMP). In some cases interleukin (IL)-1β was used as an inflammatory stimulus. Time course and dose-response relationships were evaluated to determine effects on panels of well characterized in vitro biomarkers of decidualization. RESULTS PPARβ/δ, along with ERα and PR-A and -B were expressed in human endometrial tissue and isolated ESC. GW0742 treatment enhanced hormone-mediated ESC decidualization in vitro as manifested by upregulation of prolactin, IGFBP-1, IL-11 and VEGF secretion and also increased expression of ERα, PR-A and -B and Cx43. RA treatment also increased VEGF, ERα, PR-A and -B and an active, non-phosphorylated isoform of Cx43. IL-1β and PPARβ/δ antagonists inhibited biomarkers of endometrial differentiation. CONCLUSION Ligands that activate PPARβ/δ augment the in vitro expression of biomarkers of ESC decidualization. By contrast, PPARβ/δ antagonists impaired decidualization markers. Drugs activating these receptors may have therapeutic benefits for embryonic implantation.