Extravillous Trophoblast Migration and Invasion: Impact of Environmental Chemicals and Pharmaceuticals

Hsa-miR-210-3p has been reported to be upregulated in preeclampsia (PE); however, the functions of miR-210-3p in placental development are not fully understood, and, consequently, miR-210-3p’s role in the pathogenesis of PE is still under investigation. In this study, we found that overexpression of miR-210-3p reduced trophoblast migration and invasion, extravillous trophoblast (EVT) outgrowth in first trimester explants, expression of endovascular trophoblast (enEVT) markers and the ability of trophoblast to form endothelial-like networks. In addition, miR-210-3p overexpression significantly downregulated the mRNA levels of interleukin-1B and -8, as well as CXC motif ligand 1. These cytokines have been suggested to play a role in EVT invasion and the recruitment of immune cells to the spiral artery remodeling sites. We also showed that caudal-related homeobox transcription factor 2 (CDX2) is targeted by miR-210-3p and that CDX2 downregulation mimicked the observed effects of miR-210-3p upregulation in trophoblasts. These findings suggest that miR-210-3p may play a role in regulating events associated with enEVT functions and its overexpression could impair spiral artery remodeling, thereby contributing to PE.

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Extravillous Trophoblast Migration and Invasion Assay

BIO-PROTOCOL ◽

10.21769/bioprotoc.840 ◽

2013 ◽

Vol 3 (15) ◽

Cited By ~ 3

Author(s):

Magdalena Angelova ◽

Heather Machado ◽

Kenneth Swan ◽

Cindy Morris ◽

Deborah Sullivan

Keyword(s):

Extravillous Trophoblast ◽

Migration And Invasion ◽

Invasion Assay ◽

Trophoblast Migration

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Knockdown of activated Cdc42-associated kinase inhibits human extravillous trophoblast migration and invasion and decreases protein expression of pho-Akt and matrix metalloproteinase

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2018.1515196 ◽

2018 ◽

Vol 33 (7) ◽

pp. 1125-1133 ◽

Cited By ~ 3

Author(s):

Yangming Liu ◽

Nan Shan ◽

Yu Yuan ◽

Bin Tan ◽

Chengjin He ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Protein Expression ◽

Extravillous Trophoblast ◽

Migration And Invasion ◽

Trophoblast Migration

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CRY2 suppresses trophoblast migration and invasion in recurrent spontaneous abortion

The Journal of Biochemistry ◽

10.1093/jb/mvz076 ◽

2019 ◽

Vol 167 (1) ◽

pp. 79-87 ◽

Cited By ~ 2

Author(s):

Lianzhi Wu ◽

Biheng Cheng ◽

Qian Liu ◽

Ping Jiang ◽

Jing Yang

Keyword(s):

Spontaneous Abortion ◽

Cell Model ◽

Recurrent Spontaneous Abortion ◽

Extravillous Trophoblast ◽

Matrix Metalloproteinase 2 ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Protein Levels ◽

Cryptochrome 2 ◽

Trophoblast Migration

Abstract Disruption of circadian rhythms is associated with aberrant trophoblast migration and invasion in recurrent spontaneous abortion (RSA). This study aims to explore the functional role and the mechanisms of cryptochrome 2 (CRY2), a fundamental component of the circadian clock, in regulating trophoblast migration and invasion. Human extravillous trophoblast cell line HTR-8/SVneo was used as a cell model. Cell migration and invasion were examined using wound healing assay and Transwell assay, respectively. The mRNA and protein levels were determined using quantitative real-time polymerase chain reaction and western blot, respectively. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the interaction between c-Myc to the brain and muscle ARNT-like protein 1 (BMAL1) promoter. CRY2 was highly expressed in human villous specimens of RSA. Furthermore, CRY2 overexpression impaired migration and invasion in HTR-8/SVneo cells, whereas CRY2 knockdown yielded the opposite results. Mechanistically, c-Myc bound to the BMAL1 promoter and induced BMAL1 transcription, both of which further activated matrix metalloproteinase 2/9 (MMP2/9) and facilitated migration and invasion in HTR-8/SVneo cells. CRY2 inhibited c-Myc-BMAL1 pathway and impaired migration and invasion of HTR-8/SVneo cells. Collectively, these findings demonstrate that CRY2 suppresses trophoblast migration and invasion via inhibiting c-Myc-BMAL1-MMP2/9 pathway.

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Regulation of the Matricellular Proteins CYR61 (CCN1) and NOV (CCN3) by Hypoxia-Inducible Factor-1α and Transforming-Growth Factor-β3 in the Human Trophoblast

Endocrinology ◽

10.1210/en.2009-1195 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2835-2845 ◽

Cited By ~ 36

Author(s):

Nadine Wolf ◽

Wei Yang ◽

Caroline E. Dunk ◽

Isabella Gashaw ◽

Stephen J. Lye ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Extravillous Trophoblast ◽

Migration And Invasion ◽

Ccn Proteins ◽

Low Oxygen ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Placental Perfusion ◽

Hypoxia Inducible Factor 1Α ◽

Trophoblast Migration

It is known that a hypoxic environment is critical for trophoblast migration and invasion and is fundamental for appropriate placental perfusion. Because cysteine-rich 61 (CYR61, CCN1) and nephroblastoma overexpressed (NOV, CCN3) are expressed in the extravillous trophoblast and expression levels are deregulated in preeclampsia, we investigated their regulation properties in first-trimester placental explants and in JEG3 choriocarcinoma cells upon a physiological low oxygen tension of 1–3%. In placental explants, both proteins were expressed in the extravillous trophoblast cells and were increased upon hypoxia. JEG3 cells revealed a significant up-regulation of CYR61 and NOV intracellular as well as secreted protein upon hypoxic treatment accompanied by the stabilization of the hypoxia-inducible factor-1α (HIF-1α). Treatment with dimethyloxalylglycine to mimic hypoxia and silencing of HIF-1α using small interfering RNA revealed that only the increase in intracellular protein expression seems to be dependent on HIF-1α but obviously not the secretion process. Moreover, recombinant TGF-β3 was able to further enhance the amount of intracellular CCN proteins as well as secreted CYR61 levels under hypoxia. These results indicate that low oxygen levels trigger elevation of intracellular as well as secreted CYR61 and NOV protein probably in two independent pathways. Addition of recombinant CYR61 and NOV proteins increases migration as well as invasion properties of JEG3 trophoblast cells, which strengthen their role in supporting trophoblast migration invasion properties. In summary, CYR61 and NOV are regulated by HIF-1α and TGF-β3 in the trophoblast cell line JEG3, and their enhanced secretion could be implicated in appropriate placental invasion.

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Role of ARID1A in the Regulation of Human Trophoblast Migration and Invasion

Reproductive Sciences ◽

10.1007/s43032-021-00686-0 ◽

2021 ◽

Author(s):

Meiyuan Jin ◽

Shouying Xu ◽

Jiayong Li ◽

Lu Li ◽

Chao Tang

Keyword(s):

Migration And Invasion ◽

Human Trophoblast ◽

Trophoblast Migration

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Silencing SEC5 inhibits trophoblast invasion via integrin/Ca2+ signaling

Reproduction ◽

10.1530/rep-19-0088 ◽

2020 ◽

Vol 159 (1) ◽

pp. 59-71

Author(s):

Wen-Wen Gu ◽

Long Yang ◽

Xing-Xing Zhen ◽

Yan Gu ◽

Hua Xu ◽

...

Keyword(s):

Early Pregnancy ◽

First Trimester ◽

Cytosolic Calcium ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Migration And Invasion ◽

Third Trimester ◽

Imaging Results ◽

Fetal Bovine ◽

And Migration

The invasion of maternal decidua by extravillous trophoblast (EVT) is essential for the establishment and maintenance of pregnancy, and abnormal trophoblast invasion could lead to placenta-associated pathologies including early pregnancy loss and preeclampsia. SEC5, a component of the exocyst complex, plays important roles in cell survival and migration, but its role in early pregnancy has not been reported. Thus, the present study was performed to explore the functions of SEC5 in trophoblast cells. The results showed that SEC5 expression in human placental villi at first trimester was significantly higher than it was at the third trimester, and it was abundantly localized in the cytotrophoblast (CTB) and the trophoblastic column. SEC5 knockdown was accompanied by reduced migration and invasion in HTR-8/SVneo cells. In addition, the expression and plasma membrane distribution of integrin β1 was also decreased. Furthermore, shRNA-mediated knockdown of SEC5 inhibited the outgrowth of first trimester placental explants. SEC5 and InsP3R were colocalized in the cytoplasm of HTR-8/SVneo cells, and the cell-permeant calcium chelator BAPTA-AM could significantly inhibit HTR-8/SVneo cell invasion. The Ca2+ imaging results showed that the 10% fetal bovine serum-stimulated cytosolic calcium concentration ([Ca2+]c) was not only reduced by downregulated SEC5 but also was blocked by the InsP3R inhibitor. Furthermore, either the [Ca2+]c was buffered by BAPTA-AM or the knockdown of SEC5 disrupted HTR-8/SVneo cell F-actin stress fibers and caused cytoskeleton derangement. Taken together, our results suggest that SEC5 might be involved in regulating trophoblast cell migration and invasion through the integrin/Ca2+ signal pathway to induce cytoskeletal rearrangement.

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