Center for Abnormal Placentation, Division of Maternal-Fetal Medicine and Surgery, Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ, USA.
Center for Abnormal Placentation, Division of Maternal-Fetal Medicine and Surgery, Department of Obstetrics and Gynecology, Hackensack University Medical Center, Hackensack, NJ, USA.
Placenta. 2020 Dec;102:61-66. doi: 10.1016/j.placenta.2020.01.004. Epub 2020 Jan 10.
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.
滋养层细胞侵入子宫壁被认为是妊娠建立的关键组成部分，然而，这个过程中唯一明确确定的部分是滋养层细胞（CTB）分化为侵袭性绒毛外滋养层（EVT）。侵袭的控制，包括启动和终止，尚未阐明，甚至分化的机制也不清楚。这篇综述描述了我们旨在表征驱动分化的细胞内机制的研究。我们利用异常侵袭性胎盘（AIP；胎盘植入）中观察到的过度侵袭来进一步研究这种机制。我们的结果表明，第一孕期 CTB 向 EVT 的分化是通过上皮-间充质转化（EMT）完成的，EVT 表现出一种亚稳定的间充质表型。在第三孕期，尽管 EVT 的侵袭性丧失，但这些细胞仍然表现出 EMT 的迹象，尽管程度减弱。然而，从 AIP 妊娠中分离出的 EVT 并没有表现出正常第三孕期细胞所表现出的相同程度的 EMT 减少。它们表现出更具间充质表型的特征，这与更大侵袭性的遗留有关。控制 EMT 的主调控转录因子似乎是 ZEB2（锌指 E 盒结合蛋白 2）。我们通过在 BeWo 和 JEG3 滋养层细胞系中转染 ZEB2 并证明它们变得更加星状，上调 EMT 相关基因的表达，并表现出显著增加的侵袭性，从而验证了这一点。分化机制的鉴定将使我们能够识别控制侵袭的因素以及在 AIP 和子痫前期等病理中产生异常侵袭的异常过程。
