Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors

The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualiza tion of the stroma. Previous studies established that the gene encoding hep arin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal ep ithelium solely at the site of blastocyst apposition preceding the attachme nt reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone mo rphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgeho g (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Desp ite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling protein s. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IG F-l), but not other proteins , induce many of the same discrete local responses elicited by the blastocy st, including increased localized vascular permeability, decidualization, a nd expression of Bmp2 at the sites of the beads. By contrast, the expressio n domains of Indian hedgehog (Ihh), patched, and noggin become restricted a s decidualization proceeds. Significantly, beads containing BMP-2 do not th emselves elicit an implantation response but affect the spacing of implanta tion sites induced by blastocysts cotransferred with the beads.