Epithelial-mesenchymal plasticity in trophoblast differentiation

Area of Science:

• Reproductive biology
• Developmental biology
• Cellular differentiation

Background:

• The differentiation of cytotrophoblast (CTB) into extravillous trophoblast (EVT) is crucial for human placenta development.
• This process involves a transformation from an epithelial to a mesenchymal phenotype, known as epithelial-mesenchymal transition (EMT).

Purpose of the Study:

• To explore the mechanism of CTB differentiation into invasive EVT.
• To analyze gene expression and DNA methylation patterns associated with EMT and mesenchymal-epithelial transition (MET) in trophoblast cells during pregnancy.
• To investigate the role of ZEB2 in regulating trophoblast EMT.

Main Methods:

• Gene expression analysis of EMT-associated genes in first and third trimester CTB and EVT.
• Analysis of ZEB2 transcription factor expression and its effect on trophoblast cell lines.
• DNA methylation analysis of third trimester EVT.
• Development of a trophoblast-specific EMT signature.

Main Results:

• First trimester EVT show evidence of EMT, with increased ZEB2 expression and a mesenchymal, invasive phenotype.
• Third trimester EVT exhibit MET, with reduced ZEB2 expression and a non-motile, non-proliferative mesenchymal phenotype.
• ZEB2 overexpression promotes EMT markers, mesenchymal morphology, and invasiveness in trophoblast cell lines.
• Genome-wide hypomethylation and specific gene hypermethylation were observed in third trimester EVT, suggesting regulated gene expression.
• Trophoblast cells display epithelial-mesenchymal plasticity (EMP) with dynamic shifts between EMT and MET phenotypes.

Conclusions:

• ZEB2 is a key regulator of EMT in first trimester EVT, promoting invasion.
• Trophoblast cells undergo MET in the third trimester, transitioning to a non-invasive phenotype.
• Trophoblast epithelial-mesenchymal plasticity (EMP) allows for dynamic adaptation of EVT phenotypes throughout pregnancy.
• Understanding these transitions is vital for comprehending normal placental development and identifying potential pathologies.