Membrane-Bound Peptidases Regulate Human Extravillous Trophoblast Invasion

Abstract

During human placentation, the extravillous trophoblast (EVT) invades maternal decidua and spiral arteries. However, the precise regulatory mechanisms by which EVT invasion is induced toward maternal arteries or limited within the uterus have not been well characterized. Recently, we found that dipeptidyl peptidase IV, a membrane-bound cell surface peptidase that can degrade chemokines, including RANTES, was expressed on EVT that had already ceased invasion. Another cell surface peptidase, carboxypeptidase-M, was also detected on EVT including the endovascular trophoblast in the maternal arteries. The inhibition of these peptidases increased cell invasion of choriocarcinoma-derived JEG-3 cells. On the other hand, CCR-1, a chemokine receptor for RANTES, was specifically expressed on EVT that migrated toward maternal arteries, while RANTES enhanced invasion of EVT that were isolated from primary villous explant culture. Platelets, which secrete RANTES and other chemokines, were detected among the endovascular trophoblast, and platelets were shown to enhance invasion of cultured EVT. Furthermore, a novel membrane-bound cell surface peptidase, laeverin, was found to be specifically expressed on EVT at deep sites in the maternal decidua. These findings suggest that membrane-bound peptidases regulate EVT invasion in cooperation with a chemokine system during early human placentation.