Growth factor-extracellular matrix synergy in the control of trophoblast invasion

At the periphery of the human placenta, trophoblast attaches to the uterine wall. The tissue interface contains many anchoring sites, with cytotrophob last columns that form bridges between the overlying extraembryonic (villou s) mesenchyme and the maternal decidual stroma beneath. From the periphery of these columns, large numbers of trophoblast cells detach, migrate throug h the decidua and eventually colonize and transform maternal arteries. In t his way the placenta increases and gives priority to the maternal blood sup ply to the conceptus. We have shown that when early villous tissue is expla nted on a collagen gel in serum-free medium, anchoring-site morphogenesis o ccurs. Thus, in the presence of placental mesenchyme but in the absence of maternal cells, contact with a permissive extracellular matrix (ECM) is nec essary and sufficient for cytotrophoblast column development. Proliferation of trophoblast occurs, followed by differentiation into a columnar cell ph enotype in which cells remain attached to one another and to the ECM. At th is stage, interaction between fibronectin and integrin alpha 5 beta 1 at th e cell surface stabilizes the column and the cells remain as a contiguous m ultilayered sheet. However, the addition of serum-free conditioned medium f rom first-trimester placental fibroblasts stimulates cytotrophoblast to det ach from the distal column and migrate in streams across the ECM. The remov al of insulin-like growth factor I (IGF-I) from the fibroblast medium decre ases streaming activity, whereas the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produces a. streaming phenotype. In contrast, transfo rming growth factor beta 1 (10 ng/ml) maintains the cells in a tight sheet. These results suggest the possibility of a paracrine interaction between v illous mesenchyme and cytotrophoblast in anchoring sites tal stimulate the infiltration of the maternal ECM by trophoblast. Such a mechanism would be self-limiting because the signal diminishes with distance from the placenta .