Integrin Beta 8 (ITGB8) Regulates Embryo Implantation Potentially via Controlling the Activity of TGF-B1 in Mice1

Abstract

Integrins (ITGs) are mediators of cell-cell and cell-matrix interactions, which are also associated with embryo implantation processes by controlling the interaction of blastocyst with endometrium. During early pregnancy, ITGbeta8 (ITGB8) has been shown to interact with latent transforming growth factor (TGF) beta 1 (TGFB1) at the fetomaternal interface. However, the precise role of ITGB8 in the uterus and its association with embryo implantation has not been elucidated. Therefore, we attempted to ascertain the role of ITGB8 during the window of embryo implantation process by inhibiting its function or protein expression. Uterine plasma membrane-anchored ITGB8 was augmented at peri-implantation and postimplantation stages. A similar pattern of mRNA expression was also found during the embryo implantation period. An immunolocalization study revealed the presence of ITGB8 on luminal epithelial cells along with mild expression on the stromal cells throughout the implantation period studied; however, an intense fluorescence was noted only during the peri- and postimplantation stages. Bioneutralization and mRNA silencing of the uterine Itgb8 at preimplantation stage reduced the rate/frequency of embryo implantation and subsequent pregnancy, suggesting its indispensable role during the embryo implantation period. ITGB8 can also regulate the liberation of active TGFB1 from its latent complex, which, in turn, acts on SMAD2/3 phosphorylation (activation) in the uterus during embryo implantation. This indicates involvement of ITGB8 in the embryo implantation process through regulation of activation of TGFB1.

Integrin beta8 (ITGB8) activates VAV-RAC1 signaling via FAK in the acquisition of endometrial epithelial cell receptivity for blastocyst implantation

“…Importantly, the endometrial luminal epithelial cells sense the implanted blastocyst and accommodate it for pregnancy establishment 27, 28 and ITGB3 has been vital in this process 29, 30 . Further, recently one of our study has demonstrated a prominent expression of ITGB8 in the endometrial epithelial cells 10 . However, apart from the adhesion process of integrin during the lodging process of a blastocyst on the endometrial cells to facilitate the implantation process, they also may trigger the intracellular signaling pathways via various biochemical messengers, but this needs further investigation, which is being reported in the present study.…”

“…In our recent report, we have demonstrated the expression of ITGB8 in the endometrium and it was predominant in the luminal epithelial cells, which is essential for embryo implantation process 10 . Importantly, ITGB8 controls the TGF-B activation, which is also one of the crucial signaling in the acqusition of endometrial receptivity for blastocyst implantaiton 10, 31 .…”

“…Binding of the integrins to ECM ligands trigger the formation of focal adhesions (FAs), multi-protein signaling complexes that bridge the integrin cytoplasmic tails with the actin cytoskeleton 6 . Integrin beta (ITGB) family member beta8 has been reported in the epithelial cell growth regulation 7–9 and our recent report has documented its role in the endometrial receptivity for embryo implantation process 10 , but we could not establish any detail downstream signaling in particular to the endometrial epithelial cells.…”

“…Importantly, ITGB8 controls the TGF-B activation, which is also one of the crucial signaling in the acqusition of endometrial receptivity for blastocyst implantaiton 10, 31 . However, the downstream signaling triggered by the ITGB8 in the receptive endometrial epithelial cells is still unknown.…”

Embryo–epithelium interactions during implantation at a glance

“…Function-inhibiting antibodies that target integrin αvβ3 or αvβ8 -both of which are expressed on trophectoderm as well as on receptive phase epithelium -RGD peptide and knockdown of epithelial αvβ3 can reduce embryo attachment in vitro (Kaneko et al, 2011(Kaneko et al, , 20132014a) and in vivo (Illera et al, 2000(Illera et al, , 2003Kumar et al, 2015). This implies an interaction between integrin αv and an extracellular bridging ligand (see poster) regarding attachment (Singh and Aplin, 2009).…”