The in vitro effects of triiodothyronine on epidermal growth factor-induced trophoblast function

The development of the human placenta involves a complex process of tightly regulated proliferation and invasion by extravillous trophoblast into the uterine decidua. Inadequate placentation is a feature of intrauterine growth restriction and other gestational pathology. There is some evidence that T-3 plays a role in the regulation of these processes and that T-3 may act synergistically with epidermal growth factor (EGF). The aim of this study was to define the expression of thyroid hormone receptors in extravillous trophoblast, elucidate the effects of T-3 on both proliferation and differentiation of human trophoblast cells of varying origins, and define the potential interaction between EGF and T-3 on these processes. Using immunohistochemistry, specific thyroid hormone receptor isoforms were localized in extravillous trophoblast in first- and second-trimester placental bed biopsies, indicating potential sensitivity to T-3. In studies of human trophoblast-derived cell lines and primary cultures of cytotrophoblast cells in vitro, T-3 and EGF exerted an antiproliferative effect on an extravillous-like cell line (SGHPL-4) but stimulated proliferation in JEG-3 choriocarcinoma cells. EGF enhanced survival of nonproliferative term primary cytotrophoblast cells and significantly enhanced invasion of fibrin gels by SGHPL-4 cells, an effect attenuated by T-3. Both T-3 and EGF also significantly enhanced SGHPL-4 motility. These results suggest that EGF and T-3 may act synergistically to regulate both proliferation and differentiated function of human trophoblast.