Article

Zhou, Y. et al. Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J. Clin. Invest. 99, 2139-2151

Department of Stomatology, University of California San Francisco, 94143-0512, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/1997; 99(9):2139-51. DOI: 10.1172/JCI119387
Source: PubMed

ABSTRACT

Establishment of the human placenta requires that fetal cytotrophoblast stem cells in anchoring chorionic villi become invasive. These cytotrophoblasts aggregate into cell columns and invade both the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta. Cytotrophoblasts colonizing spiral arterioles replace maternal endothelium as far as the first third of the myometrium. We show here that differentiating cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace. Cytotrophoblasts in cell columns show reduced E-cadherin staining and express VE-(endothelial) cadherin, platelet-endothelial adhesion molecule-1, vascular endothelial adhesion molecule-1, and alpha-4-integrins. Cytotrophoblasts in the uterine interstitium and maternal vasculature continue to express these receptors, and, like endothelial cells during angiogenesis, also stain for alphaVbeta3. In functional studies, alphaVbeta3 and VE-cadherin enhance, while E-cadherin restrains, cytotrophoblast invasiveness. Cytotrophoblasts expressing alpha4 integrins bound immobilized VCAM-1 in vitro, suggesting that this receptor-pair could mediate cytotrophoblast-endothelium or cytotrophoblast-cytotrophoblast interactions in vivo, during endovascular invasion. In the pregnancy disorder preeclampsia, in which endovascular invasion remains superficial, cytotrophoblasts fail to express most of these endothelial markers (Zhou et al., 1997. J. Clin. Invest. 99:2152-2164.), suggesting that this adhesion phenotype switch is required for successful endovascular invasion and normal placentation.

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    • "As a result, several groups have suggested that the transformation of the epithelial-like CTB to the invasive, mensenchymal-like EVT is akin to the epithelialemesenchymal transition (EMT) that occurs in embryonic development, wound healing and cancer metastasis [6]. Data showing integrin and metalloproteinase changes [5] [7] [8], changes in cadherin expression [9], alterations in Wnt signaling [10] and trophoblast expression of mesenchymal markers [11] or EMT biomarkers [12] support this hypothesis. These results are summarized in several reviews [13e16] where the CTB-EVT conversion process has been described as " pseudo EMT " or " metastable EMT " . "

    Full-text · Dataset · Dec 2015
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    • "As a result, several groups have suggested that the transformation of the epithelial-like CTB to the invasive, mensenchymal-like EVT is akin to the epithelialemesenchymal transition (EMT) that occurs in embryonic development, wound healing and cancer metastasis [6]. Data showing integrin and metalloproteinase changes [5] [7] [8], changes in cadherin expression [9], alterations in Wnt signaling [10] and trophoblast expression of mesenchymal markers [11] or EMT biomarkers [12] support this hypothesis. These results are summarized in several reviews [13e16] where the CTB-EVT conversion process has been described as " pseudo EMT " or " metastable EMT " . "
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    ABSTRACT: The transformation of cytotrophoblast (CTB) to extravillous trophoblast (EVT) is an essential process for placental implantation. EVT generated at the tips of the anchoring villi migrate away from the placenta and invade the endometrium and maternal spiral arteries, where they modulate maternal immune responses and remodel the arteries into high-volume conduits to facilitate uteroplacental blood flow. The process of EVT differentiation has several factors in common with the epithelial-to-mesenchymal transition (EMT) observed in embryonic development, wound healing and cancer metastasis. We hypothesized that the generation of invasive EVT from CTB was a form of EMT. We isolated paired CTB and EVT from first trimester placentae, and compared their gene expression using a PCR array comprising probes for genes involved in EMT. Out of 84 genes, 24 were down-regulated in EVT compared to CTB, including epithelial markers such as E-cadherin (À11-fold) and occludin (À75-fold). Another 30 genes were up-regulated in EVT compared to CTB including mesenchymal markers such as vimentin (235-fold) and fibronectin (107-fold) as well as the matrix metalloproteinases, MMP2 and MMP9 (357-fold, 129-fold). These alterations also included major increases in the ZEB2 (zinc finger E-box binding homeobox 2, 198-fold) and TCF4 (transcription factor 4, 18-fold) transcription factors, suggesting possible stimulatory mechanisms. There was substantial up-regulation of the genes encoding TGFbeta1 and TGFbeta2 (48-fold, 115-fold), which may contribute to the maintenance of the mesenchymal-like phenotype. We conclude that transformation of CTB to EVT is consistent with an EMT, although the differences with other types of EMT suggest this may be a unique form.
    Full-text · Article · Oct 2015 · Placenta
    • "Then, at the end of the first trimester, the trophoblastic plugs are progressively dislocated, allowing maternal blood to flow more freely and continuously within the intervillous space (Jauniaux et al., 2006). Zhou et al. (1997b) demonstrated that endovascular trophoblasts invading the spiral arterioles take on a vascular adhesion phenotype typical of endothelial cells, and subsequently showed that while proliferation of EVTs was dependent on the low oxygen environment characteristic of early gestation, differentiation into an invasive phenotype occurred in higher oxygen tensions (Genbacev et al., 1997). This group also found that EVT in women who develop preeclampsia fail to up-regulate vascular adhesion markers which may explain why endovascular invasion does not proceed beyond the superficial portions of preeclamptic uterine spiral arterioles (Zhou et al., 1997a). "
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    ABSTRACT: Reduced or absent cytotrophoblast invasion of the maternal uterine spiral arterioles is a common clinical finding in studies of pregnancies complicated by preeclampsia, suggesting that the mechanisms mediating invasion of these cells is perturbed. The placenta initially develops in a low oxygen environment of 1–2% oxygen until after the 10th week of pregnancy. During this time oxygen concentration exerts a major influence over trophoblast activity and, hypoxia inducible factors are proposed to be one of many key regulators of first trimester trophoblast behaviour. We used a global gene expression microarray approach to identify signalling pathways and hypoxia-responsive genes of interest involved in invasion of the first trimester trophoblast cell line HTR8/SVneo under hypoxic conditions where HIF-1 was active. Additionally, first trimester placental samples from different gestational age groups were labelled with anti HIF-1α and HIF-2α to evaluate whether HIFs are differentially expressed and localised across two periods of placental development: (1) early first trimester characterised by hypoxia (6–8 weeks) and (2) late first trimester after initiation of maternal blood flow into the placenta (10–12 weeks).
    No preview · Article · Oct 2015 · European journal of cell biology
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