Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells

Asako Ochiai,Atsuo Itakura,Joanne Muter,Keisuke Murakami,Akemi Matsumoto,Keiji Kuroda,Yuko Ikemoto,Satoru Takeda,Jan J Brosens,Rie Ozaki

doi:10.1038/s41419-019-1511-7

Abstract

Pregnancy critically depends on the transformation of the human endometrium into a decidual matrix that controls embryo implantation and placenta formation, a process driven foremost by differentiation and polarization of endometrial stromal cells into mature and senescent decidual cells. Perturbations in the decidual process underpin a spectrum of prevalent reproductive disorders, including implantation failure and early pregnancy loss, emphasizing the need for new therapeutic interventions. Resveratrol is a naturally occurring polyphenol, widely used for its antioxidant and anti-inflammatory properties. Using primary human endometrial stromal cell (HESC) cultures, we demonstrate that resveratrol has anti-deciduogenic properties, repressing not only the induction of the decidual marker genes PRL and IGFBP1 but also abrogating decidual senescence. Knockdown of Sirtuin 1, a histone deacetylase activated by resveratrol, restored the expression of IGFBP1 but not the induction of PRL or senescence markers in decidualizing HESCs, suggesting involvement of other pathways. We demonstrate that resveratrol interferes with the reprogramming of the retinoic acid signaling pathway in decidualizing HESCs by accelerating down-regulation of cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor (RAR). Notably, knockdown of CRABP2 or RAR in HESCs was sufficient to recapitulate the anti-deciduogenic effects of resveratrol. Thus, while resveratrol has been advanced as a potential fertility drug, our results indicate it may have detrimental effects on embryo implantation by interfering with decidual remodeling of the endometrium.

Highlights

Resveratrol (3,5,4′-trihydroxystilbene), a natural polyphenolic compound found in grapes, nuts, and berries, is widely studied because of its antioxidative, anti-inflammatory and insulin-sensitizing properties[1,2]
ΜM of resveratrol significantly inhibited the induction of PRL, a widely used decidual marker gene, in primary cultures treated with 8-bromoadenosine 3′5′-cyclic AMP and progesterone (P4) for 4 days (Supplementary Figure S1)
Recent studies demonstrated that primary human endometrial stromal cell (HESC) polarize into two subpopulations upon decidualization, representing mature and acutely senescent decidual cells[15,28]

Summary

Introduction

Resveratrol (3,5,4′-trihydroxystilbene), a natural polyphenolic compound found in grapes, nuts, and berries, is widely studied because of its antioxidative, anti-inflammatory and insulin-sensitizing properties[1,2]. It is a potent activator of Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent histone. During the mid-luteal phase, the human endometrium starts to remodel intensely, heralding a transient window for embryo implantation. This implantation window coincides with the differentiation of endometrial stromal cells into specialized decidual cells. Interleukin-15 (IL-15) activated uterine natural killer (uNK) cells target and eliminate senescent decidual cells via granule exocytosis, enabling the cycling endometrium to transition into a gestational tissue upon embryo implantation[15]

Methods

Results

Conclusion