ABSTRACT
Research question
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)?
Design
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).
Results
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).
Conclusions
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.
Graphical Abstract
Graphical Abstract
Keywords
Abbreviations:
AGEs (Advanced Glycation End-products), hEEO (human endometrial epithelial organoids), BMI (body mass index)To read this article in full you will need to make a payment
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Biography
Jennifer Hutchison completed her PhD under the primary supervision of Professor Lois Salamonsen at the Hudson Institute of Medical Research. Her research aims to understand how the uterine fluid microenvironment influences maternal-fetal communication and endometrial receptivity.
Article info
Publication history
Accepted:
January 24,
2023
Received in revised form:
January 23,
2023
Received:
September 18,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Key message: Advanced Glycation Endproducts (AGEs) are elevated in the obese uterine environment, and compromise preimplantation embryo development. Obesity-associated AGEs promote an inflammatory uterine environment, and antioxidants mitigate anti-proliferative effects in cell lines. Investigation of targeted reduction of AGEs before conception and therapeutic antioxidant use may improve fertility outcomes for women with elevated intrauterine AGEs.
Identification
Copyright
© 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
