Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems

The invasion of an extravillous trophoblast (EVT) into maternal decidual tissues, especially towards maternal spiral arteries, is an essential process in the human placental formation and subsequent normal fetal development. However, the precise regulatory mechanisms to induce EVT invasion towards arteries and/or to protect EVT from further invasion are not well understood. We found that a chemokine receptor, CCR1, was specifically expressed on EVT migrating towards maternal arteries. Using EVT isolated from a primary villous explant culture, RANTES, which is one of the ligands for CCR1, was shown to enhance EVT invasion. Furthermore, we observed that the platelets were deposited among intravascular EVT and platelet-derived soluble factors, which contained RANTES, enhanced EVT invasion. On the one hand, dipeptidyl peptidase IV (DPPIV), which can metabolize RANTES on the cell surface, was expressed on non-invading EVT and was demonstrated to suppress EVT invasion. In contrast, laeverin/aminopeptidase Q, which is specifically expressed on EVT, was shown to induce EVT invasion. Also, CD9 which is a cell surface marker of platelets and a regulator of integrin function was expressed on EVT and gene knockdown of the CD9 molecule enhanced EVT invasion. These findings suggest that the chemokine-chemokine receptor, chemokine-peptidase, and CD9-integrin systems play important roles in the regulation of EVT invasion during early human placental formation.