The unusual ability of placental trophoblast (TB) cells to adhere to and then invade the uterine wall is an integral component first of implantation and subsequently of placentation We have a longstanding interest in the adhesive properties of the human mononuclear Tbs, termed cytotrophoblasts (CTBs) , that invade the uterine wall. Previously we focused on members of three of the four major cell adhesion systems: integrins, cadherins, and immunoglobulin superfamily receptors. We found that CTBs have a remarkable ability to modulate their adhesion molecule repertoire as they differentiate and invade. In essence, they assume many of the cell surface properties of endothelial cells. We also study interactions mediated by the fourth major cell adhesion system- carbohydrate binding receptors, termed lectins, and their mucin- oligosacharide ligands. Recently we discovered that a salivary mucin (MUC7) carries sialyl Le/x oligosaccharides that confer biology activity to selectin ligands, which in turn mediate leukocyte rolling and tethering in laminar flow. We hypothesized and provide that MUC7 mediates neutrophil adhesion in the range of shear stresses encountered at oral surfaces, a noel function for mucins. In this context we noted work from other groups that shows uterine expression of MUC1, which also carries sialyl Lex epitopes, is up-regulated during the human implantation window. Together these observations suggested that selectins and their mucin-oligosaccharide ligands could play novel roles in TB adhesion to the uterus. Therefore, we looked for expression at the maternal fetal- interface of selectin receptors. Immunolocalization studies showed that early gestation TBs stained strongly for all three: the leukocyte, platelet and endothelial selectins. To our knowledge this is the first description of selectin expression in cells other than hemangioblast descendants. Accordingly, we propose to test the hypothesis that CTB interactions with the uterine wall are mediated by components of the same adhesion system that governs the rolling and tethering of blood cells. Specifically, we will (Aim 1) characterize, at the human fetal-maternal interface, CTB expression of selectins and uterine expression of their ligands;
and (Aim 2) test the functional relevance of these receptor-ligand interactions in CTB adhesion in laminar flow. The results will advance our understanding of mechanisms that govern critical steps in human placentation. Additionally, these data will lead to collaborative studies to identify animal models for in vivo testing of the functional relevance of selectin-ligand interactions in implantation and placentation. We envision that expression of components of this adhesion system could be up- or down-regulated in clinical conditions associated with abnormal endometrial differentiation, faulty implantation and/or poor pregnancy outcome.
