ENDOGLIN REGULATES TROPHOBLAST DIFFERENTIATION ALONG THE INVASIVE PATHWAY IN HUMAN PLACENTAL VILLOUS EXPLANTS

Successful invasion of the maternal vascular system by trophoblast cel ls is a prerequisite for the establishment of a normal hemochorial pla centa. Transforming growth factor-beta (TGF beta) has been implicated in the regulation of trophoblast invasiveness into the uterus. Endogli n is a component of the TGF beta receptor complex that binds beta 1 an d beta 3 isoforms and is expressed at high levels on syncytiotrophobla st throughout pregnancy and is also transiently up-regulated on extrav illous trophoblasts differentiating along the invasive pathway. We inv estigated the role of endoglin in a serum-free human villous explant c ulture system that allows the study of trophoblast outgrowth, migratio n, and invasion and mimics events occurring in anchoring villi during the first trimester of gestation. Addition to explant cultures from 5- 8 weeks gestation of a monoclonal antibody to endoglin or of antisense endoglin oligonucleotides significantly stimulated trophoblast outgro wth and migration. These responses were specific, as incubation of exp lants with nonimmune IgG or sense and scrambled oligonucleotides had n o effect. Antisense endoglin-induced trophoblast outgrowth and migrati on were accompanied by cell division of villous-associated trophoblast s within the proximal region of the forming column and by the characte ristic switch in integrins observed in anchoring villi in situ. Treatm ent of villous explants with antibody and antisense oligonucleotides t o endoglin also resulted in an increased fibronectin release into the culture medium. The stimulatory effect of antisense endoglin on fibron ectin production was overcome by the addition of exogenous TGF beta 2, but not TGF beta 1 and -beta 3. These findings suggest that endoglin expression in the transition from polarized to nonpolarized trophoblas ts in anchoring villi is necessary for mediation of the inhibitory eff ect of TGF beta 1 and/or TGF beta 3 on trophoblast differentiation alo ng the invasive pathway.