UDP-glucose, a cellular danger signal, and nucleotide receptor P2Y14 enhance the invasion of human extravillous trophoblast cells

Preeclampsia (PE) remains the leading cause of maternal and fetal morbidity and mortality. Excessive apoptosis of the placenta and poor remodeling of spiral arteries caused by insufficient invasion of trophoblast cells into uterus have been implicated in the pathogenesis of PE. Accumulating evidence showed that heat shock protein 20 (HSP20) is closely associated with the proliferation, apoptosis, and metastasis of tumor cells. However, little is known about whether HSP20 plays a role in the development of PE. In this study, we detected the apoptosis index and the expressions of HSP20 and apoptosis-associated proteins in the placentas from PE and normal pregnancies. We found that HSP20 was reversely related to the apoptosis rate and the levels of proapoptotic proteins. Moreover, we identified that HSP20 could suppress the proliferation and apoptosis of trophoblast cells, turning them into a more invasive phenotype. Additionally, H2O2-induced oxidative stress was significantly alleviated, and several key proteins on the Akt signaling pathway were upregulated in HSP20-overexpressing trophoblast cells. These findings strongly suggested that HSP20 might play a role in the remodeling of spiral arteries through affecting the invasiveness of extravillous trophoblast cells via Akt signaling pathway, and the dysregulation of it might contribute to the pathophysiology of PE.

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Blocking Epidermal Growth Factor Receptor Signaling in HTR-8/SVneo First Trimester Trophoblast Cells Results in Dephosphorylation of PKBα/AKT and Induces Apoptosis

Obstetrics and Gynecology International ◽

10.1155/2011/896896 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

J. Bolnick ◽

L. Albitar ◽

L. L. Laidler ◽

R. Abdullah ◽

K. K. Leslie

Keyword(s):

Protein Phosphorylation ◽

Global Analysis ◽

Growth Factor Receptor ◽

First Trimester ◽

Extravillous Trophoblast ◽

Signaling Proteins ◽

Trophoblast Cells ◽

Novel Technology ◽

Epidermal Growth ◽

Growth Factor Receptor Signaling

We identified a major peptide signaling target of EGF/EGFR pathway and explored the consequences of blocking or activating this pathway in the first trimester extravillous trophoblast cells, HTR-8/SVneo. A global analysis of protein phosphorylation was undertaken using novel technology (Kinexus Kinetworks) that utilizes SDS-polyacrylamide minigel electrophoresis and multi-lane immunoblotting to permit specific and semiquantitative detection of multiple phosphoproteins. Forty-seven protein phosphorylation sites were queried, and the results reported based on relative phosphorylation at each site. EGF- and Iressa-(gefitinib, ZD1839, an inhibitor of EGFR) treated HTR-8/SVneo cells were subjected to immunoblotting and flow cytometry to confirm the phosphoprotein screen and to assess the effects of EGF versus Iressa on cell cycle and apoptosis. EGFR mediates the phosphorylation of important signaling proteins, including PKBα/AKT. This pathway is likely to be central to EGFR-mediated trophoblast survival. Furthermore, EGF treatment induces proliferation and inhibits apoptosis, while Iressa induces apoptosis.

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Human cytotrophoblast populations studied by monoclonal antibodies using single and double biotin-avidin-peroxidase immunocytochemistry.

Journal of Histochemistry & Cytochemistry ◽

10.1177/33.10.3900197 ◽

1985 ◽

Vol 33 (10) ◽

pp. 977-983 ◽

Cited By ~ 40

Author(s):

B H Butterworth ◽

T Y Khong ◽

Y W Loke ◽

W B Robertson

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Mhc Class I ◽

Hla Antigens ◽

Extravillous Trophoblast ◽

Reaction Products ◽

Primary Sequence ◽

Trophoblast Cells ◽

Double Labeling ◽

Human Trophoblast

Single and double biotin-avidin-peroxidase immunocytochemical methods in conjunction with an anti-trophoblast monoclonal antibody 18B/A5 and an anti-HLA-A,B,C monoclonal antibody W6/32 were used to study various human trophoblast populations. Several combinations of peroxidase substrates were tried in the double-labeling procedure. It was concluded that the use of 4-chloro-1 naphthol to develop the primary sequence peroxidase and of 3-amino-9-ethyl carbazole for the second sequence peroxidase was the most suitable. The significant findings were: Monoclonal antibody 18B/A5 proved to be a useful marker for villous as well as nonvillous trophoblast, which facilitated the identification of these cells particularly in the placental bed. The expression of MHC Class I antigens was not confined to extravillous trophoblast but these antigens were also demonstrable on the villous cytotrophoblast proliferating to form new primary villi. Double labeling revealed that many of these cells, particularly those furthest away from the mesenchymal core, expressed both trophoblast and HLA antigens as shown by a mixing of the colors produced by the two reaction products. A large number of these HLA-A,B,C, positive trophoblast cells were found to infiltrate deep into the uterine myometrium. The hypothesis was put forward that these fetal cells could be the ones that are responsible for maternal sensitization.

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Regulation of expression of p57KIP2 gene in extravillous trophoblast cells

Placenta ◽

10.1016/j.placenta.2014.08.074 ◽

2014 ◽

Vol 35 (10) ◽

pp. A20

Author(s):

Hirokazu Usui ◽

Jia Qu ◽

Emiri Nakata ◽

Hiroshi Kaku ◽

Shinsuke Hanawa ◽

...

Keyword(s):

Extravillous Trophoblast ◽

Trophoblast Cells ◽

Regulation Of Expression

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Intersection of regulatory pathways controlling hemostasis and hemochorial placentation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111267118 ◽

2021 ◽

Vol 118 (50) ◽

pp. e2111267118

Author(s):

Masanaga Muto ◽

Damayanti Chakraborty ◽

Kaela M. Varberg ◽

Ayelen Moreno-Irusta ◽

Khursheed Iqbal ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Differentiation ◽

Cell Invasion ◽

Cell Development ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Cell Phenotype ◽

Trophoblast Cells ◽

Rat Models ◽

Endovascular Trophoblast

Hemochorial placentation is characterized by the development of trophoblast cells specialized to interact with the uterine vascular bed. We utilized trophoblast stem (TS) cell and mutant rat models to investigate regulatory mechanisms controlling trophoblast cell development. TS cell differentiation was characterized by acquisition of transcript signatures indicative of an endothelial cell-like phenotype, which was highlighted by the expression of anticoagulation factors including tissue factor pathway inhibitor (TFPI). TFPI localized to invasive endovascular trophoblast cells of the rat placentation site. Disruption of TFPI in rat TS cells interfered with development of the endothelial cell-like endovascular trophoblast cell phenotype. Similarly, TFPI was expressed in human invasive/extravillous trophoblast (EVT) cells situated within first-trimester human placental tissues and following differentiation of human TS cells. TFPI was required for human TS cell differentiation to EVT cells. We next investigated the physiological relevance of TFPI at the placentation site. Genome-edited global TFPI loss-of-function rat models revealed critical roles for TFPI in embryonic development, resulting in homogeneous midgestation lethality prohibiting analysis of the role of TFPI as a regulator of the late-gestation wave of intrauterine trophoblast cell invasion. In vivo trophoblast-specific TFPI knockdown was compatible with pregnancy but had profound effects at the uterine–placental interface, including restriction of the depth of intrauterine trophoblast cell invasion while leading to the accumulation of natural killer cells and increased fibrin deposition. Collectively, the experimentation implicates TFPI as a conserved regulator of invasive/EVT cell development, uterine spiral artery remodeling, and hemostasis at the maternal–fetal interface.

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