Mesenchymally-derived Insulin-like growth factor 1 provides a paracrine stimulus for trophoblast migration

BACKGROUND: Trophoblast migration into maternal decidua is essential for normal pregnancy. It occurs in a defined time window, is spatially highly restricted, and is aberrant in some pathological pregnancies, but the control mechanisms are as yet ill-defined. At the periphery of the placenta, chorionic villi make contact with decidua to form specialised anchoring sites that feed interstitially migrating cytotrophoblast into the placental bed. RESULTS: Explants of first trimester mesenchymal villi on collagen type I developed cytotrophoblast outgrowths from the villous tips. However, in medium changed daily, cells did not progress to a migratory phenotype, remaining instead as a contiguous multi-layered sheet. This suggested the need for another migration stimulus. To test the possibility that this might arise from mesenchymal cells, serum-free conditioned medium from first trimester placental fibroblasts was added to explant cultures. Cytotrophoblasts were stimulated to migrate in streams across the gel. Affinity depletion of Insulin-like growth factor from fibroblast medium reduced streaming activity, while the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produced a streaming phenotype. IGF receptor type 1 (IGFR1) was present on cells in the columns, and streaming could be inhibited by antibody to this receptor. IGF-II and activin, known stimulators of cytotrophoblast migration, were also active in this model. CONCLUSIONS: These data suggest a paracrine interaction between villous mesenchyme and the cytotrophoblast in anchoring sites that stimulates trophoblast infiltration of decidua. Such a signal would be self-limiting since it diminishes with distance from the placenta. This is a novel mechanism in placental development.