ERBB receptor expression and ligand-induced activity during extravillous trophoblast differentiation

Human embryo implantation is a complex process requiring the attachment of an activated blastocyst to receptive endometrial epithelium and subsequent trophoblast invasion throughout the first trimester of pregnancy. Chemokines, including fractalkine (FKN), MCP-3, HCC-1 and MIP-1β, are produced by human endometrial epithelial and decidual cells with maximal production around the time of implantation/early pregnancy.1,2 Chemokine and receptor expression was characterized in cell types at the human maternal–trophoblast interface. Highly abundant expression of chemokine receptors CX3CR1 and CCR1 was observed in first trimester placenta and in trophoblast cells.3 We hypothesized that CX3CR1 and CCR1 ligands (FKN, MCP-3, HCC-1 and MIP-1β) produced by endometrial epithelial and decidualised stromal cells at the time of implantation promote migration of human trophoblast. We aimed to localize specific chemokine receptors in human first trimester tissue, and to determine whether trophoblast migration could be stimulated by the endometrium and by chemokines. Cellular localisation of specific receptors was assessed by immunohistochemistry in human first trimester implantation sites. Using an in vitro assay, trophoblast migration was assessed in response to human endometrial epithelial (HEEC) and decidualised stromal cells (DESC) (serum-free) conditioned medium and to recombinant human FKN, MCP-3, HCC-1 and MIP-1β. CX3CR1 and CCR1 protein was localised to the vascular extravillous trophoblast (EVTs), but not to the invading interstitial EVTs, with weak staining on the syncytium. Significant migration of cells occurred in response to conditioned media from HEEC and DESC. FKN, MIP-1β and HCC-1, but not MCP-3 also promoted significant trophoblast migration. Neutralizing antibodies for FKN and MIP-1β but not MCP-3 significantly reduced migration to conditioned media, indicating that at least these two chemokines contributed to the effects. These data support a role for endometrial derived chemokines in promoting human trophoblast migration. (1)Jones et al. (2004). JCEM 89(12), 6155–6167.(2)Hannan et al. (2004). Reprod. Fert. Devel. 16(Suppl.), A225, p. 78.(3)Hannan et al. (2004). JCEM 89(12), 6119–6129.

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Trophoblast lineage specification, differentiation and their regulation by oxygen tension

Journal of Endocrinology ◽

10.1530/joe-17-0402 ◽

2018 ◽

Vol 236 (1) ◽

pp. R43-R56 ◽

Cited By ~ 24

Author(s):

Ching-Wen Chang ◽

Anna K Wakeland ◽

Mana M Parast

Keyword(s):

Oxygen Tension ◽

First Trimester ◽

Arterial Blood Flow ◽

Extravillous Trophoblast ◽

Low Oxygen ◽

Epithelial Stem Cells ◽

Placental Development ◽

Trophoblast Differentiation ◽

Arterial Blood ◽

Low Oxygen Tension

Development of the early embryo takes place under low oxygen tension. Under such conditions, the embryo implants and the trophectoderm, the outer layer of blastocyst, proliferate, forming the cytotrophoblastic shell, the early placenta. The cytotrophoblasts (CTBs) are the so-called epithelial ‘stem cells’ of the placenta, which, depending on the signals they receive, can differentiate into either extravillous trophoblast (EVT) or syncytiotrophoblast (STB). EVTs anchor the placenta to the uterine wall and remodel maternal spiral arterioles in order to provide ample blood supply to the growing fetus. STBs arise through CTB fusion, secrete hormones necessary for pregnancy maintenance and form a barrier across which nutrient and gas exchange can take place. The bulk of EVT differentiation occurs during the first trimester, before the onset of maternal arterial blood flow into the intervillous space of the placenta, and thus under low oxygen tension. These conditions affect numerous signaling pathways, including those acting through hypoxia-inducible factor, the nutrient sensor mTOR and the endoplasmic reticulum stress-induced unfolded protein response pathway. These pathways are known to be involved in placental development and disease, and specific components have even been identified as directly involved in lineage-specific trophoblast differentiation. Nevertheless, much controversy surrounds the role of hypoxia in trophoblast differentiation, particularly with EVT. This review summarizes previous studies on this topic, with the intent of integrating these results and synthesizing conclusions that resolve some of the controversy, but then also pointing to remaining areas, which require further investigation.

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The effect of anticardiolipin IgG on extravillous trophoblast differentiation

Fertility and Sterility ◽

10.1016/s0015-0282(03)01740-0 ◽

2003 ◽

Vol 80 ◽

pp. 289

Author(s):

Andrew J. Drakeley ◽

Stephen Mountfield ◽

Roy G. Farquharson ◽

Charles R. Kingsland ◽

Gill Vince ◽

...

Keyword(s):

Extravillous Trophoblast ◽

Trophoblast Differentiation

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HYPEROSMOLARITY INDUCES CAVEOLAE DISRUPTION IMPAIRING HUMAN EXTRAVILLOUS TROPHOBLAST DIFFERENTIATION

Placenta ◽

10.1016/j.placenta.2021.07.161 ◽

2021 ◽

Vol 112 ◽

pp. e50

Author(s):

Julieta Reppetti ◽

Yollyseth Medina ◽

Mariana Farina ◽

Alicia E. Damiano ◽

Nora Martinez

Keyword(s):

Extravillous Trophoblast ◽

Trophoblast Differentiation

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Hypoxia Directs Human Extravillous Trophoblast Differentiation in a Hypoxia-Inducible Factor–Dependent Manner

American Journal Of Pathology ◽

10.1016/j.ajpath.2016.11.018 ◽

2017 ◽

Vol 187 (4) ◽

pp. 767-780 ◽

Cited By ~ 39

Author(s):

Anna K. Wakeland ◽

Francesca Soncin ◽

Matteo Moretto-Zita ◽

Ching-Wen Chang ◽

Mariko Horii ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Extravillous Trophoblast ◽

Dependent Manner ◽

Trophoblast Differentiation

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ErbB receptor expression and growth response to heregulin beta 1 in five ovarian carcinoma lines.

International Journal of Oncology ◽

10.3892/ijo.14.6.1169 ◽

1999 ◽

Author(s):

J C Pegues ◽

B Kannan ◽

K Stromberg

Keyword(s):

Ovarian Carcinoma ◽

Growth Response ◽

Receptor Expression ◽

Erbb Receptor

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Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity

10.1101/669796 ◽

2019 ◽

Author(s):

Jenna Treissman ◽

Victor Yuan ◽

Jennet Baltayeva ◽

Hoa T. Le ◽

Barbara Castellana ◽

...

Keyword(s):

Lysyl Oxidase ◽

Atmospheric Oxygen ◽

Extravillous Trophoblast ◽

Low Oxygen ◽

Placental Development ◽

Trophoblast Differentiation ◽

Expression Of Genes ◽

Summary Statement ◽

Insight Into

ABSTRACTEarly placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary StatementLow oxygen promotes extravillous trophoblast differentiation

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