Extravillous trophoblast cell invasion is promoted by the CD44–hyaluronic acid interaction

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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A 3-dimensional microfluidic platform for modeling human extravillous trophoblast invasion and toxicological screening

Lab on a Chip ◽

10.1039/d0lc01013h ◽

2021 ◽

Author(s):

Yong Pu ◽

Jeremy Gingrich ◽

Almudena Veiga-Lopez

Keyword(s):

Cell Invasion ◽

Dynamic Environment ◽

Cell Interaction ◽

Microfluidic System ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Trophoblast Invasion ◽

Toxicological Screening ◽

Microfluidic Platform ◽

3 Dimensional

A novel 3D microfluidic system for placenta trophoblast cell invasion and cell-to-cell interaction studies under dynamic environment conditions.

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Interferon‐γ inhibits extravillous trophoblast cell invasion by a mechanism that involves both changes in apoptosis and protease levels

The FASEB Journal ◽

10.1096/fj.06-6616com ◽

2006 ◽

Vol 20 (14) ◽

pp. 2512-2518 ◽

Cited By ~ 89

Author(s):

Gendie E. Lash ◽

Harry A. Otun ◽

Barbara A. Innes ◽

Maureen Kirkley ◽

Leandro De Oliveira ◽

...

Keyword(s):

Cell Invasion ◽

Interferon Γ ◽

Trophoblast Cell ◽

Extravillous Trophoblast

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Placenta-specific miRNA miR-520c modulates CD44-mediated extravillous trophoblast cell invasion

Placenta ◽

10.1016/j.placenta.2014.06.215 ◽

2014 ◽

Vol 35 (9) ◽

pp. A66-A67

Author(s):

Hironori Takahashi ◽

Akihide Ohkuchi ◽

Takami Takizawa ◽

Shigeki Matsubara ◽

Rie Usui ◽

...

Keyword(s):

Cell Invasion ◽

Trophoblast Cell ◽

Extravillous Trophoblast

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ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2016517118 ◽

2021 ◽

Vol 118 (10) ◽

pp. e2016517118

Author(s):

Kaela M. Varberg ◽

Khursheed Iqbal ◽

Masanaga Muto ◽

Mikaela E. Simon ◽

Regan L. Scott ◽

...

Keyword(s):

Cell Differentiation ◽

Cell Invasion ◽

Cell Lineage ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Sequencing Analysis ◽

Spiral Artery ◽

Trophoblast Cells ◽

Junctional Zone ◽

Artery Remodeling

Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of ASCL2 and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.

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Role of Interleukin 8 in Uterine Natural Killer Cell Regulation of Extravillous Trophoblast Cell Invasion

Placenta ◽

10.1016/j.placenta.2010.04.012 ◽

2010 ◽

Vol 31 (7) ◽

pp. 595-601 ◽

Cited By ~ 46

Author(s):

L.G. De Oliveira ◽

G.E. Lash ◽

C. Murray-Dunning ◽

J.N. Bulmer ◽

B.A. Innes ◽

...

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Cell Invasion ◽

Killer Cell ◽

Trophoblast Cell ◽

Interleukin 8 ◽

Extravillous Trophoblast ◽

Cell Regulation ◽

Uterine Natural Killer

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108. FUNCTIONAL ROLE OF HtrA3 IN TROPHOBLAST CELL INVASION DURING HUMAN PLACENTAL DEVELOPMENT

Reproduction Fertility and Development ◽

10.1071/srb09abs108 ◽

2009 ◽

Vol 21 (9) ◽

pp. 27

Author(s):

H. Singh ◽

G. Nie

Keyword(s):

Cell Invasion ◽

Stromal Cells ◽

Functional Role ◽

First Trimester ◽

Trophoblast Cell ◽

Extravillous Trophoblast ◽

Placental Development ◽

Decidual Cells

Controlled invasion of extravillous trophoblast (EVT) through the maternal decidua is important for placental development and function. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy. It is highly expressed in first trimester in most trophoblast cell types, but not in the invading interstitial trophoblast. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumor-suppressors. We hypothesized that HtrA3 is an inhibitor of trophoblast invasion and is down-regulated in invading EVTs, while up-regulation of decidual HtrA3 controls the process. The current study investigated HtrA3 expression in human endometrial stromal cells (HESC) during decidualization in vitro and whether HtrA3 inhibits EVT cell invasion. Stromal cells isolated from human endometrium were decidualized in vitro with estrogen, progesterone and cAMP. Quantitative RT-PCR and western showed HtrA3 mRNA and protein expression was significantly increased in decidualized HESC compared to controls. Indirect immunofluorescence showed homogeneous pattern and increase in intensity of HtrA3 staining in decidualized HESC compared to non-decidualized cells. HTR-8 cells derived from first trimester of pregnancy EVT showed higher levels of HtrA3 mRNA expression compared to other human choriocarcinoma cell lines (AC-1M88, AC-1M32, JEG-3 and BeWo). Both intracellular and extracellular HtrA3 staining was observed in HTR8 cells. Functional role of HtrA3 in cell invasion was determined in HTR-8 cells using an in vitro invasion assay. Exogenous addition of mutant HtrA3 (inhibitor) resulted in a significant increase in HTR-8 cells invading through matrigel coated membrane compared with controls. TGFβ-1 (as positive control) completely inhibited invasion of HTR-8 cells. HtrA3 is tightly regulated during decidualization of HESC in vitro. Inhibition of HtrA3 activity in trophoblastic HTR-8 cells increased invasiveness supporting its functional role during placental development.

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