Human Endometrial Stromal Cell Differentiation is Stimulated by PPAR[beta]/[delta] 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 present study we analyzed the effects of pero...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2020-09, Vol.105 (9), p.1
Main Authors: Yu, Jie, Berga, Sarah L, Zou, Wei, Rajakumar, Augustine, Man, Mingfei, Sidell, Neil, Taylor, Robert N
Format: Article
Language:English
Subjects:
Cell differentiation
Cyclic adenylic acid
Estradiol
Fatty acids
Interleukins
Progesterone
Prolactin
Protein binding
Tretinoin
Vascular endothelial growth factor
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Summary: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 present study we analyzed the effects of peroxisome-proliferator-activated receptor [beta]/[delta] (PPAR[beta]/[delta]) activation on established cellular biomarkers of human endometrial differentiation (decidualization). Objective: The objective of this work is to test the effects of PPAR[beta]/[delta] ligation on human endometrial cell differentiation. Design: Isolated primary human endometrial stromal cells (ESCs) were treated with synthetic (GW0742) or natural (all trans-retinoic acid, RA) ligands of PPAR[beta]/[delta], and also with receptor antagonists (GSK0660, PT-S58, and ST247) in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP [3',5'-cyclic adenosine 5'-monophosphate]). In some cases interleukin (IL)-1[beta] 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: PPAR[beta]/[delta], along with estrogen receptor [alpha] (ER[alpha]) and PR-A and PR-B, were expressed in human endometrial tissue and isolated ESCs. GW0742 treatment enhanced hormone-mediated ESC decidualization in vitro as manifested by upregulation of prolactin, insulin-like growth factor-binding protein 1, IL-11, and vascular endothelial growth factor (VEGF) secretion and also increased expression of ER[alpha], PR-A and PR-B, and connexin 43 (Cx43). RA treatment also increased VEGF, ER[alpha], PR-A, and PR-B and an active, nonphosphorylated isoform of Cx43. IL-1 [beta] and PPAR[beta]/[delta] antagonists inhibited biomarkers of endometrial differentiation. Conclusion: Ligands that activate PPAR[beta]/[delta] augment the in vitro expression of biomarkers of ESC decidualization. By contrast, PPAR[beta]/[delta] antagonists impaired decidualization markers. Drugs activating these receptors may have therapeutic benefits for embryonic implantation. (J Clin Endocrinol Metab 105: 1-13, 2020) Freeform/Key Words: uterus, decidualization, nuclear receptors, fatty acids, retinoic acid
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgaa413