Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype

• Published in: Developmental biology 2004-02, Vol.266 (2), p.223-237
• Main Authors: Leach, Richard E, Kilburn, Brian, Wang, Jun, Liu, Zitao, Romero, Roberto, Armant, D.Randall
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion; Cell Division; Cell Line; Cell Movement - physiology; Chorionic Villi - metabolism; Culture Techniques; Cytotrophoblast; Epidermal Growth Factor - metabolism; ErbB Receptors - metabolism; Extracellular matrix; Female; Growth factors; Growth Substances - metabolism; Heparin-binding EGF-like Growth Factor; HER/ErbB Receptors; Humans; Integrin alpha1 - metabolism; Integrin alpha6 - metabolism; Integrins; Intercellular Signaling Peptides and Proteins; Invasion; Motility; Phenotype; Placentation; Preeclampsia; Pregnancy; Pregnancy Trimester, First; Proliferation; Protein Isoforms - metabolism; Signal Transduction - physiology; Trophoblasts - cytology; Trophoblasts - physiology
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2003.09.026

Cytotrophoblasts of the anchoring villi convert during human placentation from a transporting epithelium to an invasive, extravillous phenotype that expresses a distinct repertoire of adhesion molecules. Developing extravillous trophoblasts accumulate heparin-binding EGF-like growth factor (HB-EGF), a multifunctional cytokine, which binds HER1 and HER4 of the human EGF receptor (HER/ErbB) family. HB-EGF is downregulated in placentae of women with preeclampsia, a disorder associated with deficient trophoblast invasion, raising important questions about its physiological impact on cytotrophoblasts. Addition of HB-EGF during explant culture of first-trimester chorionic villi enhanced extravillous trophoblast differentiation and invasive activity. Using a first-trimester human cytotrophoblast line, the potential for autocrine and paracrine regulation of the developing trophoblast was established based on the expression of all four HER isoforms, as well as HB-EGF and related growth factors. HB-EGF did not alter proliferation, but initiated extravillous differentiation, with decreased α6 integrin expression, increased α1, and elevated cell migration. Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching. We conclude that HER-mediated autocrine and paracrine signaling by HB-EGF or other EGF family members induces cytotrophoblast differentiation to an invasive phenotype.