Senescence of stromal cells contributes to endometrium dysfunction and embryo implantation failure

Abstract

Successful implantation requires two-sided interaction between genetically normal embryo and properly prepared endometrium. At the cellular level the latter means hormone-regulated differentiation of endometrial stromal cells (ESCs) into decidual ones that create appropriate microenvironment for invading embryo. Impaired decidualization is proved to mediate implantation failures. Here we elicited ESCs’ senescence as the cause for disturbed decidualization of endometrial stroma and impaired blastocyst implantation. Ability to decidualize and to accept modeled blastocysts inversely correlated with senescence in patients’ ESCs lines. Reduced hormonal responsiveness of senescent ESCs led to inappropriate decidualization dynamics resulting in altered receptivity, disturbed ligand-receptor interaction with trophoblasts and modified architecture of extracellular matrix what hindered blastocysts’ invasion. Furthermore, senescent ESCs caused ‘bystander’ quenching of decidual reaction in adjacent cells reinforcing dysfunction of stromal compartment. Implementation of senomorphics reducing senescence phenotype diminished adverse effects of senescent ESCs on decidualization and implantation using both in vitro models and patients’ lines, what suggests a promising strategy to increase in vitro fertilization efficacy.

Higher Oxidative Stress in Endometriotic Lesions Upregulates Senescence-Associated p16ink4a and β-Galactosidase in Stromal Cells

“…Stromal cells from patients without endometriosis showed minor changes. Interestingly, mesenchymal cells isolated from the eutopic endometrium of non-receptive patients presented higher senescent markers (p21, p16, and SA-β-gal activity), showing a negative correlation between senescence and decidualization/implantation [ 19 , 20 ]. In endometriosis, recent studies have shown that defective implantation is associated with a decrease in pregnancy rates [ 56 ], demonstrating a relationship between impaired decidualization in endometriosis, and fertility.…”

“…In endometriosis, recent studies have shown that defective implantation is associated with a decrease in pregnancy rates [ 56 ], demonstrating a relationship between impaired decidualization in endometriosis, and fertility. The hypothesis raised by the authors suggest that endometrial stromal cells that are senescent are irresponsive to hormone stimuli and have difficulties differentiating properly during the mesenchymal to epithelial transition; thus, senescence would impair decidualization by reducing the proliferative capacity [ 19 ].…”

“…Similarly, senescence markers present in the endometriotic lesion [ 13 ] can alter tissue homeostasis, contributing to the maintenance of lesions and the characteristic inflammatory milieu of the disease. Previous studies have linked the increase in endometrial stromal cells’ senescence to implantation failure and impaired decidualization [ 19 , 20 ], but no association with endometriosis or endometriosis-associated infertility is known.…”

The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy

“…uNK cells can recognize and eliminate pro-inflammatory senescent decidual cells via the CD44 receptor, thus promoting successful implantation [ 121 ]. The application of drugs (senomorphics) that inhibit senescence-related secretory phenotypes during the proliferative phase of the menstrual cycle may offer a potential strategy for enhancing successful embryo implantation [ 122 ]. It is worth noting that evaluating the senescence index of decidual NK cells at different stages of embryonic development could provide further insights into the role of senescence in placental development.…”