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Epithelial-mesenchymal transition during extravillous trophoblast differentiation.

ABSTRACT: A successful pregnancy depends on the intricate and timely interactions of maternal and fetal cells. Placental extravillous cytotrophoblast invasion involves a cellular transition from an epithelial to mesenchymal phenotype. Villous cytotrophoblasts undergo a partial epithelial to mesenchymal transition (EMT) when differentiating into extravillous cytotrophoblasts and gain the capacity to migrate and invade. This review summarizes our current knowledge regarding known regulators of EMT in the human placenta, including the inducers of EMT, upstream transcription factors that control EMT and the downstream effectors, cell adhesion molecules and their differential expression and functions in pregnancy pathologies, preeclampsia (PE) and fetal growth restriction (FGR). The review also describes the research strategies that were used for the identification of the functional role of EMT targets in vitro. A better understanding of molecular pathways driven by placental EMT and further elucidation of signaling pathways underlying the developmental programs may offer novel strategies of targeted therapy for improving feto-placental growth in placental pathologies including PE and FGR.

SUBMITTER: E Davies J

PROVIDER: S-EPMC4951171 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Epithelial-mesenchymal transition during extravillous trophoblast differentiation.

E Davies Jessica J Pollheimer Jürgen J Yong Hannah E J HE Kokkinos Maria I MI Kalionis Bill B Knöfler Martin M Murthi Padma P

Cell adhesion & migration 20160412 3

A successful pregnancy depends on the intricate and timely interactions of maternal and fetal cells. Placental extravillous cytotrophoblast invasion involves a cellular transition from an epithelial to mesenchymal phenotype. Villous cytotrophoblasts undergo a partial epithelial to mesenchymal transition (EMT) when differentiating into extravillous cytotrophoblasts and gain the capacity to migrate and invade. This review summarizes our current knowledge regarding known regulators of EMT in the hu ...[more]

PMID: 27070187

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Project description:Study questionDoes the upregulation of the zinc finger E-box binding homeobox 2 (ZEB2) transcription factor in human trophoblast cells lead to alterations in gene expression consistent with an epithelial-mesenchymal transition (EMT) and a consequent increase in invasiveness?Summary answerOverexpression of ZEB2 results in an epithelial-mesenchymal shift in gene expression accompanied by a substantial increase in the invasive capacity of human trophoblast cells.What is known alreadyIn-vivo results have shown that cytotrophoblast differentiation into extravillous trophoblast involves an epithelial-mesenchymal transition. The only EMT master regulatory factor which shows changes consistent with extravillous trophoblast EMT status and invasive capacity is the ZEB2 transcription factor.Study design, size, durationThis study is a mechanistic investigation of the role of ZEB2 in trophoblast differentiation. We generated stable ZEB2 overexpression clones using the epithelial BeWo and JEG3 choriocarcinoma lines. Using these clones, we investigated the effects of ZEB2 overexpression on the expression of EMT-associated genes and proteins, cell morphology and invasive capability.Participants/materials, setting, methodsWe used lentiviral transduction to overexpress ZEB2 in BeWo and JEG3 cells. Stable clones were selected based on ZEB2 expression and morphology. A PCR array of EMT-associated genes was used to probe gene expression. Protein measurements were performed by western blotting. Gain-of-function was assessed by quantitatively measuring cell invasion rates using a Transwell assay, a 3D bioprinted placenta model and the xCelligenceTM platform.Main results and the role of chanceThe four selected clones (2 × BeWo, 2 × JEG3, based on ZEB2 expression and morphology) all showed gene expression changes indicative of an EMT. The two clones (1 × BeWo, 1 × JEG3) showing >40-fold increase in ZEB2 expression also displayed increased ZEB2 protein; the others, with increases in ZEB2 expression <14-fold did not. The two high ZEB2-expressing clones demonstrated robust increases in invasive capacity, as assessed by three types of invasion assay. These data identify ZEB2-mediated transcription as a key mechanism transforming the epithelial-like trophoblast into cells with a mesenchymal, invasive phenotype.Large scale dataPCR array data have been deposited in the GEO database under accession number GSE116532.Limitations, reasons for cautionThese are in-vitro studies using choriocarcinoma cells and so the results should be interpreted in view of these limitations. Nevertheless, the data are consistent with in-vivo findings and are replicated in two different cell lines.Wider implications of the findingsThe combination of these data with the in-vivo findings clearly identify ZEB2-mediated EMT as the mechanism for cytotrophoblast differentiation into extravillous trophoblast. Having characterized these cellular mechanisms, it will now be possible to identify the intracellular and extracellular regulatory components which control ZEB2 and trophoblast differentiation. It will also be possible to identify the aberrant factors which alter differentiation in invasive pathologies such as preeclampsia and abnormally invasive placenta (AKA accreta, increta, percreta).Study funding and competing interest(s)Funding was provided by the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Surgery at Hackensack Meridian Health, Hackensack, NJ. The 3D bioprinted placental model work done in Drs Kim and Fisher's labs was supported by the Children's National Medical Center. The xCELLigence work done in Dr Birge's lab was supported by NIH CA165077. The authors declare no competing interests.

Project description:Trophectoderm cells of the blastocyst are the precursor of the placenta that is comprised of trophoblast, endothelial and smooth muscle cells. Since trophoectoderm cells are epithelial in nature, epithelial mesenchymal transition (EMT) of trophoblast stem (TS) cells might play pivotal role in placental morphogenesis. However, the molecular regulation of EMT during placental development and trophoblast differentiation still remained elusive. In this report, we sought to identify the molecular signature that regulates EMT during placental development and TS cell differentiation in mice. On E7.5 onwards the TS cells, located in the ectoplacental cone (EPC), rapidly divide and differentiate leading to formation of placenta proper. Using a real time PCR based array of functional EMT transcriptome with RNA from mouse implantation sites (IS) on E7.5 and E9.5, it was observed that there was an overall reduction of EMT gene expression in the IS as gestation progressed from E7.5 to E9.5 albeit the levels of EMT gene expression were substantial on both days. Further validation of array results using real time PCR and western blot analysis showed significant decrease in EMT-associated genes that included (a) transcription factors (Snai2, Zeb1, Stat3 and Foxc2), (b) extracellular matrix and cell adhesion related genes (Bmp1, Itga5, Vcan and Col3A1), (c) migration and motility- associated genes (Vim, Msn and FN1) and (d) differentiation and development related genes (Wnt5b, Jag1 and Cleaved Notch-1) on E9.5. To understand whether EMT is an ongoing process during placentation, the EMT-associated signatures genes, prevalent on E 7.5 and 9.5, were analysed on E12.5, E14.5 and E17.5 of mouse placenta. Interestingly, expression of these EMT-signature proteins were significantly higher at E12.5 though substantial expressions was observed in placenta with progression of gestation from mid- to late. To evaluate whether TS cells have the potential to undergo EMT ex vivo, TS cells were subjected to EMT induction, which was confirmed using morphological analysis and marker gene expression. Induction of EMT in TS cells showed similar gene expression profile of placental EMT. These results have broad biological implications, as inadequate mesenchymal transition leading to improper trophoblast-vasculogenic mimicry leads to placental pathophysiology and pregnancy failure.

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Epithelial-mesenchymal transition during extravillous trophoblast differentiation.

Publications

Epithelial-mesenchymal transition during extravillous trophoblast differentiation.

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