Evaluating the effect of ovine placental extract on early embryonic development and incidence of early pregnancy loss after embryo transfer in recipient mares

Abstract

Advanced Glycation End-products (AGEs) are elevated in the uterine environment of obese infertile women. Can their detrimental effects on endometrial epithelial cells be mitigated with therapeutics, and recapitulated in a more physiologically relevant primary model (organoids)?Human endometrial epithelial cells (ECC-1) were exposed to AGEs at concentrations physiologically representative of the lean and obese uterine fluid, and three potential therapeutics: 25 nM RAGE antagonist FPS-ZM1, 100 μM metformin, and a combination of antioxidants (10 μM N-acetyl-L-cysteine, 10 μM N-acetyl-L-carnitine, and 5 μM α-lipoic acid). Real time cell analysis (xCelligence) determined the rate of adhesion and proliferation. Proliferation of organoid derived cells, and secretion of cytokines from organoids was characterized in the presence of AGEs (n=5). Uterine fluid of women undergoing assisted reproduction was profiled for AGEs-associated inflammatory markers (n ≥ 67 for each correlation).ECC-1 proliferation was reduced by obese versus lean AGEs and vehicle control (P = 0.04), and restored to lean conditions by antioxidants. AGEs influenced organoid derived primary endometrial epithelial cell proliferation in a donor dependent manner. AGEs increased organoid secretion of proinflammatory cytokines, including CXCL16 (P < 0.01). Clinically, CXCL16 correlated positively to maternal BMI (R = 0.26, P = 0.02) and intrauterine glucose (R = 0.74, P < 0.0001).Physiologically relevant concentrations of AGEs alter endometrial epithelial cell function. Antioxidants restore the rate of proliferation of AGEs-treated endometrial epithelial cells (ECC-1). Primary endometrial epithelial cells, cultured as organoids, demonstrate altered proliferation and cytokine secretion in the presence of AGEs equimolar with the obese uterine fluid.