Pregnancy

Epidermal Growth Factor Stimulation of Trophoblast Differentiation Requires MAPK11/14(p38 MAP Kinase) Activation

Abstract
Cultured human term villous cytotrophoblasts (CT) have been reported to be nonproliferating but differentiate when exposed to epidermal growth factor (EGF). We here show that CT differentiate into chorionic gonadoptropin (beta-hCG/CGB) expressing cells when cultured with medium alone. Addition of EGF decreases CGB secretion and prolongs production for up to 13 days. EGF stimulates the phosphorylation (activation) of the signaling intermediate p38 (MAPK11/14) and blocking phosphorylation pharmacologically with either SB203580 or SB202190 strongly inhibited spontaneous and EGF-stimulated secretion of CGB. In addition EGF-stimulated fusion of cytotrophoblasts into syncytial units was strongly inhibited by SB203580. EGF upregulated trophoblast proliferation (measured by bromodeoxyuridine uptake) and SB203580 increases this after 5 days. In agreement with this observation, EGF and SB203580 increased expression of the G1-phase specific gene cyclin-D1 (CCND1) and SB203580 down-modulated its inhibitor p21 (CDKN1A). When added to villous explant cultures, EGF did nothing to the pattern of CGB secretion but addition of SB203580 prevented the normal surge in secretion during syncytial regeneration over days 3 to 7. These data support the hypothesis that EGF-stimulated cytotrophoblast differentiation to syncytium requires MAPK11/14 activation, that cytotrophoblast proliferation can be stimulated in culture by EGF and enhanced by MAPK11/14 inhibition with a consequent reduction of differentiation.

Key words: Pregnancy • Human chorionic gonadotropin • Placenta • Syncytiotrophoblast • Trophoblast

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