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.