MEF2 Transcription Factors Regulate Human Trophoblast Invasion and Differentiation [33P

Abstract

INTRODUCTION: Adverse pregnancy outcomes, including preeclampsia and preterm birth, two significant causes of maternal and fetal morbidity and mortality, are associated with placental trophoblast dysfunction. Myocyte enhancer factor 2 (MEF2) transcription factors play an important role in cell differentiation and invasion in various cell types and tissues. The objective of our study is to explore the role of MEF2 in the invasion/differentiation of trophoblasts in normal placental development and preeclampsia. METHODS: Human cytotrophoblasts (CTBs) were isolated from term placentas and used to analyze the expression of MEF2 transcription factors and MEF2-dependent cell signaling. The effect of MEF2 on human trophoblast invasion/differentiation and its underlying mechanisms were examined in two trophoblast cell lines: HTR8/SVneo (first trimester human villous-derived) and BeWo (choriocarcinoma CTB-like) cells. RESULTS: MEF2 isoforms are differentially expressed in the CTBs of first and third trimester human placentas. MEF2D and 2B are highly expressed in first trimester trophoblasts. Introduction of MEF2D into HTR8/SVneo promotes cell invasion and migration. The invasive capacity is impeded by exogenous expression of dominant negative MEF2. MEF2A is a major isoform of MEF2 in term CTBs and is required for proper CTB differentiation into syncytiotrophoblasts. During in vitro CTB differentiation, p38 MAPK activity was detected for days 1-4, and diminished for days 5-6 suggesting that p38 MAPK signaling is essential for CTB differentiation but not for the maintenance of syncytiotrophoblasts. CONCLUSION: Our studies suggest individual MEF2 family members differentially regulate trophoblast invasion/differentiation. Dysregulation of MEF2 signaling may be associated with placenta-related pregnancy disorders, including preeclampsia.