Implantation of the Human Embryo Requires Rac1-Dependent Endometrial Stromal Cell Migration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 42; pp. 16189 - 16194
• Main Authors: Grewal, Seema, Carver, Janet G., Ridley, Anne J., Mardon, Helen J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21-10-2008; National Acad Sciences
• Subjects: Adult; B lymphocytes; Biological Sciences; Blastocyst; Cell adhesion & migration; Cell Movement; Cell Survival; Cells; Cells, Cultured; Coculture Techniques; Embryo Implantation; Embryology; Embryos; Endometrium - cytology; Endometrium - enzymology; Enzyme Activation; Epithelial cells; Female; Genes; Humans; Middle Aged; Pregnancy; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Small interfering RNA; Stromal cells; Stromal Cells - cytology; Stromal Cells - enzymology; Trophoblasts; Trophoblasts - cytology; Trophoblasts - enzymology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0806219105

Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.