Inhibition of Histone Deacetylase Activity in Human Endometrial Stromal Cells Promotes Extracellular Matrix Remodelling and Limits Embryo Invasion

Abstract

Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.

Human aqueous humor levels of transforming growth factor-β2: Association with matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases

“…In four-week-old guinea pigs, it was demonstrated that the retinal levels of the TGF-β2 protein are highly correlated with ocular refraction and axial length (22). TGF-β2 is a key factor in the progression of myopia development and axial elongation; however, reports of its expression in experimental myopia have been controversial as animal studies have demonstrated increases and decreases (22)(23)(24)(25)(26). It appears that the changes in TGF-β2 expression during the development of myopia are species-and tissue-specific (22-24,25,27).…”

PARP1 during embryo implantation and its upregulation by oestradiol in mice

“…It is well-known that the uterine epithelium undergoes remodelling at the site of the implanting embryo/blastocyst (Schlafke et al 1985, Welsh & Enders 1991, Ramathal et al 2011, Estella et al 2012. The proliferating stromal cells differentiate to form the uterine interface with the placenta, which is referred to as the decidua (Bell 1983), and decidualisation is essential for successful reproduction (Lydon et al 1995, Robb et al 1998.…”

In-vitro model systems for the study of human embryo–endometrium interactions

“…Even simpler models using decidualizing endometrial stromal cells in co-culture with trophoblast cells or trophoblast-cell-conditioned medium have also been reported Hess et al, 2007). Studies employing a co-culture model with mouse embryos and decidualizing human endometrial stromal cells to study embryo-endometrium interactions revealed the importance of endometrial stromal cell integrins in blastocyst development (outgrowth) and differentiation following attachment (Shiokawa et al, 1996) and showed that endometrial stromal cell histone deacetylase may promote trophoblast spreading of a day-4 hatched mouse embryo (as well as endometrial stromal cell migration and Jeg-3 trophoblast invasion) (Estella et al, 2012). In another heterologous in-vitro co-culture model, it was shown that inhibition of endometrial stromal cell motility suppressed mouse blastocyst invasion into the monolayer (Grewal et al, 2008).…”