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Expression of MEF2 transcription factors in human placenta and involvement in trophoblast invasion and differentiation
Author(s) -
Li Lucy,
Gong Xiaoming,
Rubin Lewis P
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.692.8
Subject(s) - trophoblast , biology , microbiology and biotechnology , placenta , syncytiotrophoblast , cellular differentiation , immunology , andrology , pregnancy , genetics , medicine , gene , fetus
The important and common adverse pregnancy outcome, preeclampsia, is characterized by placental trophoblast dysfunction and insufficient (shallow) trophoblast uterine invasion/remodeling during early pregnancy. Myocyte enhancer factor 2 (MEF2) family transcription factors play an important role in cell differentiation and invasion in a variety of cell types and tissues. The objective of this study is to explore the role of MEF2s in trophoblast differentiation and uterine invasion in normal placental development and preeclampsia. Methods Human cytotrophoblasts (CTBs) were isolated from term placentas by mechanical and enzymatic digestion and purified using Percoll gradient centrifugation and differential adhesion. Highly purified (>95%) CTBs in acute cultures (1–4 d) were used to analyze expression of MEF2 isoforms and MEF2‐dependent cell signaling pathways. The effects of MEF2 on human trophoblast invasion and differentiation and cellular pathways were examined principally in two relevant human trophoblast cell lines: HTR8/SVneo (first trimester human extravillous trophoblast phenotype) and BeWo (choriocarcinoma CTB‐like) cells. Invasion/migration was evaluated by Transwell (including chemotactic) invasion and “scratch” migration 2D assays; differentiation was assessed by trophoblast syncytial formation and expression of trophoblast differentiation genes. Results MEF2 isoforms are differentially expressed in first and third trimester placental trophoblast. In particular, MEF2D and 2B are highly expressed during first trimester placental development. In other experiments, transient overexpression of MEF2D in HTR8/SVneo cells promotes trophoblast invasion and migration. This invasive property is blocked by exogenous expression of a dominant negative MEF2. In contrast, MEF2A is the major isoform expressed in term trophoblast. MEF2A expression is associated with CTB differentiation into syncytiotrophoblast; transient overexpression of MEF2A enhances cytodifferentiation/syncytia formation. Based on p38 MAPK null experimental animals, p38 is the principal upstream regulator of MEF2. During in vitro differentiation of primary human CTB cultures, we found the course of p38 activity (phosphorylation) parallels MEF2A expression. Placental tissues obtained from pre‐eclamptic and normal (non‐pre‐eclamptic) pregnancies exhibit differences in MEF2 isoform expression. Conclusion These findings suggest individual MEF2 family members differentially regulate trophoblast invasion and differentiation. Dysregulation of MEF2 expression or signaling in early pregnancy may be associated with placenta‐related pregnancy disorders, including preeclampsia. Support or Funding Information Seed grant from Laura W. Bush Institute for Women's Health, Texas Tech University Health Sciences Center