Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype.
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 alpha6 integrin expression, increased alpha1, 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.
Leach
Richard E
RE
Department of Obstetrics and Gynecology, CS Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201-1415, USA.
Kilburn
Brian
B
Wang
Jun
J
Liu
Zitao
Z
Romero
Roberto
R
Armant
D Randall
DR
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002824:Chorionic Villi / Q000378:metabolism; D046508:Culture Techniques; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006133:Growth Substances / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D039423:Integrin alpha1 / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D010641:Phenotype; D010929:Placentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D020033:Protein Isoforms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology*
D006133:Growth Substances; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D039423:Integrin alpha1; D039503:Integrin alpha6; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D004815:Epidermal Growth Factor; D066246:ErbB Receptors