Induction of Differentiated Trophoblast Function by Epidermal Growth Factor: Relation of Immunohistochemically Detected Cellular Epidermal Growth Factor Receptor Levels*

Abstract

The effects of epidermal growth factor (EGF) on the production and secretion of hCG and human placental lactogen (hPL) by cultured placental tissues were investigated in relation to immunohistochemical measurements of cellular EGF receptor levels in the placenta. Explants of trophoblastic tissues obtained from normal early and term placentas were cultured in the presence or absence of EGF (100 ng/mL) with or without processing inhibitors (bacitracin, 1 mg/mL; colchicine, 100 microM; chloroquine, 100 microM) for 5 days, with EGF present for the first 2 days. Addition of EGF to the medium increased the release of hCG, hCG alpha, and hPL by the cultured early placental tissues. This EGF-stimulated hCG, hCG alpha, and hPL release was markedly inhibited by concomitant treatment with processing inhibitors. The time course of EGF effects indicated that the EGF-stimulated increase in hCG alpha secretion required a lag period of approximately 1 day, whereas significant increases in hCG and hPL secretion became apparent only after 3 days of EGF treatment. By contrast, in term placental tissues EGF stimulated only hCG alpha and hPL release, with a lag period of approximately 3 days. A possible direct action of EGF on the cultured placental tissues was reinforced by the immunohistochemical demonstration of EGF receptors in the placenta. When determined using the avidin/biotin immunoperoxidase method with monoclonal antibody to the mouse EGF receptor, EGF receptors were found predominantly on the syncytiotrophoblasts. Immunohistochemical measurements of cellular EGF receptor levels in the syncytiotrophoblasts revealed remarkably higher levels in early placenta compared to those in midterm and term placentas. Since EGF is likely to interact with its receptor, the lesser biological effects of EGF in cultures of term placental tissues may be due to the lower cellular EGF receptor levels in term placenta. These results demonstrate that EGF, via its receptors on the syncytiotrophoblasts, stimulates the release of both hCG and hPL in normal early placenta. They also suggest that EGF may play a significant role in the induction and regulation of the differentiated function of trophoblasts.

Changes in the expression and cytological localization of betacellulin and its receptors (ErbB-1 and ErbB-4) in the trophoblasts in human placenta over the course of pregnancy

“…ErbB-1 in very early placentas was immunolocalized in C-cells, whereas ErbB-1 in early, mid and term placentas was immunolocalized in S-cells. These results are consistent with our previous reports using immunohistochemical analysis (6,31). These findings imply that BTC in S-cells may act in a paracrine fashion in very early placentas and in an autocrine fashion in early and mid placentas via ErbB-1 in villous trophoblasts.…”

“…In our previous study regarding the biological effect of EGF in human placenta, we found that EGF in C-cells stimulates trophoblast proliferation in very early placentas, whereas EGF in S-cells stimulates and regulates differentiated trophoblast function in early placentas (8,32). It is evident that EGF induces the differentiation in explants of trophoblastic tissues obtained from normal early placentas (31) and in long term serumfree culture of isolated trophoblasts (33). Little information is, however, available regarding the role of BTC on villous trophoblasts in early placentas.…”

Characterization and differentiation of human first trimester placenta trophoblastic cells in culture

“…As a function of culture time, a parallel study was performed to determine the level of secreted intact hCG and its free a and J3 subunits, using specific monoclonal antibodies and radiometric assay (Bellet et al, 1986;Ozturk et al, 1987). In contrast to data obtained from either term placenta cultured cells (Kliman et al, 1986), or from first trimester explant cultures (Maruo et al, 1987) (Jameson et al, 1987;Zhou et al, 1987;Nulsen et al, 1988). Moreover, the addition of cAMP stimulated the secretion of hPL by cultured cells, in contrast to previous results obtained for term placenta (Zeitler et al, 1983).…”

Epidermal Growth Factor-Mediated Activation of the Map Kinase Cascade Results in Altered Expression and Function of Abcg2 (Bcrp)

“…It is known that EGF plays a vital role in differentiation of human cytotrophoblasts (Maruo et al, 1987;Morrish et al, 1997). These cells act as the progenitor cells of syncytiotrophoblasts, which form the outer layer of placental villi representing the structure of placenta that is free floating in maternal blood.…”