Human Endometrial Stromal Cell Differentiation is Stimulated by PPARβ/δ Activation: New Targets for Infertility?
Adult
Cell Differentiation
/ drug effects
Cells, Cultured
Decidua
/ drug effects
Endometrium
/ cytology
Female
Humans
Infertility, Female
/ drug therapy
Ligands
Molecular Targeted Therapy
/ methods
PPAR delta
/ agonists
PPAR-beta
/ agonists
Stromal Cells
/ drug effects
Sulfones
/ pharmacology
Thiazoles
/ pharmacology
Thiophenes
/ pharmacology
Up-Regulation
/ drug effects
decidualization
fatty acids
nuclear receptors
retinoic acid
uterus
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
26
02
2020
accepted:
22
06
2020
pubmed:
1
7
2020
medline:
25
2
2021
entrez:
29
6
2020
Statut:
ppublish
Résumé
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 β/δ (PPARβ/δ) activation on established cellular biomarkers of human endometrial differentiation (decidualization). The objective of this work is to test the effects of PPARβ/δ ligation on human endometrial cell differentiation. Isolated primary human endometrial stromal cells (ESCs) 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, 100 nM progesterone, and 0.5 mM dibutyryl cAMP [3',5'-cyclic adenosine 5'-monophosphate]). 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. PPARβ/δ, along with estrogen receptor α (ERα) 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 ERα, PR-A and PR-B, and connexin 43 (Cx43). RA treatment also increased VEGF, ERα, PR-A, and PR-B and an active, nonphosphorylated isoform of Cx43. IL-1β and PPARβ/δ antagonists inhibited biomarkers of endometrial differentiation. 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.
Identifiants
pubmed: 32594141
pii: 5864417
doi: 10.1210/clinem/dgaa413
pmc: PMC7373326
pii:
doi:
Substances chimiques
GSK0660
0
Ligands
0
PPAR delta
0
PPAR-beta
0
Sulfones
0
Thiazoles
0
Thiophenes
0
(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
4PZK9FJC4Z
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NICHD NIH HHS
ID : R01 HD055379
Pays : United States
Organisme : NICHD NIH HHS
ID : U01 HD066439
Pays : United States
Informations de copyright
© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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