Trophoblast invasion: Lessons from abnormally invasive placenta (placenta accreta)

Abstract

The invasion of the uterine wall by extravillous trophoblast is acknowledged as a crucial component of the establishment of pregnancy however, the only part of this process that has been clearly identified is the differentiation of cytotrophoblast (CTB) into the invasive extravillous trophoblast (EVT). The control of invasion, both initiation and termination, have yet to be elucidated and even the mechanism of differentiation is unclear. This review describes our studies which are designed to characterize the intracellular mechanisms that drive differentiation. We have used the over-invasion observed in abnormally invasive placenta (AIP; placenta accreta) to further interrogate this mechanism. Our results show that first trimester CTB to EVT differentiation is accomplished via an epithelial-mesenchymal transition (EMT), with EVT displaying a metastable, mesenchymal phenotype. In the third trimester, while the invasiveness of the EVT is lost, these cells still demonstrate signs of the EMT, albeit diminished. EVT isolated from AIP pregnancies do not however, show the same degree of reduction in EMT shown by normal third trimester cells. They exhibit a more mesenchymal phenotype, consistent with a legacy of greater invasiveness. The master regulatory transcription factor controlling the EMT appears, from the observational data, to be ZEB2 (zinc finger E-box binding protein 2). We verified this by overexpressing ZEB2 in the BeWo and JEG3 trophoblast cell lines and showing that they became more stellate in shape, up-regulated the expression of EMT-associated genes and demonstrated a substantially increased degree of invasiveness. The identification of the differentiation mechanism will enable us to identify the factors controlling invasion and those aberrant processes which generate the abnormal invasion seen in pathologies such as AIP and preeclampsia.

Keywords: Accreta; Differentiation; Epithelial-mesenchymal transition; Invasion; Trophoblast.

Fig. 1.

Models of extravillous trophoblast trans-uterine access. The figure shows the potential pathways for extravillous trophoblast (EVT) movement across the decidua from the anchoring villous tip into the myometrium. The figure shows normal pregnancy (A), a pregnancy where uterine damage, such as a Caesarean section, has left a scar across the uterus (B) and a pregnancy where the decidual cell population is altered in terms of either numbers or function (C).

Fig. 2.

The trophoblast epithelial-mesenchymal transition (EMT) spectrum. The spectrum of the EMT reaches from epithelial to mesenchymal. Cytotrophoblast are at the epithelial end, while first trimester EVT are situated well towards, but not at, the mesenchymal pole. Third trimester EVT show a regression, back along the spectrum towards the epithelial (cytotrophoblastic) end. EVT obtained from AIP pregnancies do not show the same degree of regression and are placed towards the mesenchymal end of the spectrum compared to third trimester normal or placenta previa controls.