Human trophoblast epithelial-mesenchymal transition in abnormally invasive placenta†

Abstract

Differentiation of first trimester human placental cytotrophoblast (CTB) from an anchorage-dependent epithelial phenotype into the mesenchymal-like invasive extravillous trophoblast (EVT) is crucial in the development of the maternal-fetal interface. We showed previously that differentiation of first trimester CTB to EVT involves an epithelial-mesenchymal transition (EMT). Here we compare the epithelial-mesenchymal characteristics of CTB and EVT derived from normal third trimester placenta or placenta previa versus abnormally invasive placenta (AIP). CTB and EVT were isolated from normal term placenta or placenta previa following Caesarean section and EVT from AIP following Caesarean hysterectomy. Cell identity was validated by measurement of cytokeratin-7 and HLA-G. Comparing normal term CTB with EVT from normal term placenta or placenta previa for differential expression analysis of genes associated with the EMT showed changes in >70% of the genes probed. While demonstrating a mesenchymal phenotype relative to CTB, many of the gene expression changes in third trimester EVT were reduced relative to the first trimester EVT. We suggest that third trimester EVT are in a more constrained, metastable state compared to first trimester equivalents. By contrast, EVT from AIP demonstrate characteristics that are more mesenchymal than normal third trimester EVT, placing them closer to first trimester EVT on the EMT spectrum, consistent with a more invasive phenotype.

The role of DNA methylation in human trophoblast differentiation

“…Similar characteristics are found in cancer cells, and may result from similar molecular circuits involved in EMT and tumour development, which have been suggested to be regulated by epigenetic factors [22,45,46]. Previous data has shown that first trimester placental lysates and cytotrophoblasts are hypomethylated in gene blocks more closely related to cancer phenotypes (some of which were enriched for EMT) compared to third trimester samples [47]. Corresponding gene expression differences in EMT pathways in first versus third trimester placentae have also been reported, and together this data likely represents key gestational differences in placentation, as the majority of EVT differentiation and invasion occurs in the first half of pregnancy [22].…”

The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

“…A major pathway that causes EVT invasion is epithelial to mesenchymal transition (EMT) [57] which is known to be regulated by NFκB [58,59]. During EMT, cells change their shape, adhesion molecules, and polarity to become invasive and drive cell migration [55].…”

Preliminary RNA‑microarray analysis of long non‑coding RNA expression in abnormally invasive placenta

“…Other ECM components, such as decorin and biglycan, were reported to be involved in placental invasion (20). In addition, ECM elasticity may direct cellular differentiation, including the epithelial-mesenchymal transition (EMT), and studies have indicated that trophoblast EMT has an important role in AIP (21,22). MMPs in the ECM are able remodel the ECM to facilitate EMT, promoting cell specification during embryonic and placental development (23,24).…”