3.3.1. Adhesion Molecules Mediating Blastocyst Adhesion

Following apposition, stable adhesion of the blastocyst to the endometrium occurs, mediated by the interaction between several receptors and ligands (Figure 2B). Over the last decades, several of these ligands and receptors have been identified. It has been observed that both the pinopodes of the endometrial epithelium and the trophectoderm of the blastocyst express the integrin αvβ3, together with the endometrial expression of its ligand, the glycoprotein osteopontin (OPN). Their expression during the WOI suggests a role in implantation [160,244,245], and the binding between integrin αvβ3 and its ligand OPN might mediate the stable adhesion between the trophoblast and the endometrium [246]. Using an in vitro model of implantation, Genbacev et al. suggested that trophoblast adhesion to the uterine wall is also mediated by L-selectin expressed on the surface of the trophoblast cells, and uterine epithelial oligosaccharide ligands, such as HECA-452 and MECA-79 [247,248]. More recently it has been also demonstrated that the transmembrane glycoprotein MUC1, abundantly expressed at the apical surface of uterine epithelium under the control of progesterone, acts as a scaffold mediating the binding between L-selectin and their ligands [249].

The adhesion of the blastocyst to the endometrium is also promoted by the expression of adhesion molecules, such as cadherins. The presence of endothelial cadherin (E-cadherin) in both the trophoblasts and endometrial epithelium, regulated by progesterone, indicates that it may play an important role in blastocyst adhesion to the endometrium [250]. As trophoblast cells proliferate, differentiate and invade the stroma, they downregulate E-cadherin and increase osteoblast cadherin (OB-cadherin) [251,252]. This temporal expression of OB-cadherin in the endometrial epithelium suggests that this adhesion molecule later mediates trophoblast–endometrium interactions. Blastocyst adhesion is also favored by the expression of the glycoproteic receptor CD98 on the surface of endometrial cells, which is normally involved not only in amino acids transport but also in cell fusion [253,254]. Using two human endometrial cell lines characterized by low and high receptivity, Dominguez et al. demonstrated that CD98 receptor is significantly associated with the receptive phenotype. In human endometrial samples, CD98 expression was spatially restricted to the apical surface of endometrial cells and temporally restricted to the WOI. Treatment of primary endometrial epithelial cells with hCG, 17-β-estradiol, LIF, or EGF increases expression of CD98, greatly enhancing murine blastocyst adhesion, while its siRNA-mediated depletion reduced blastocyst adhesion rate [255].
