Peptide hormone ELABELA enhances extravillous trophoblast differentiation, but placenta is not the major source of circulating ELABELA in pregnancy

Danai Georgiadou,Jeske M Bij De Weg,Marjon A De Boer,Willemijn H M Ranzijn,Marie Van Dijk,Carolien N H Abheiden,Tanja G M Vrijkotte,Souad Boussata,Sanne Hillenius,Esther A M Kuijper,Leah E A Root,Cornelis B Lambalk,Gijs B Afink,Johanna I P De Vries

doi:10.1038/s41598-019-55650-5

Danai Georgiadou, Jeske M Bij De Weg + Show 12 more

Open Access

https://doi.org/10.1038/s41598-019-55650-5

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Journal: Scientific Reports	Publication Date: Dec 1, 2019
Citations: 18	License type: open-access

Affiliation: Amsterdam University Medical Centers

Abstract

Preeclampsia is a frequent gestational hypertensive disorder with equivocal pathophysiology. Knockout of peptide hormone ELABELA (ELA) has been shown to cause preeclampsia-like symptoms in mice. However, the role of ELA in human placentation and whether ELA is involved in the development of preeclampsia in humans is not yet known. In this study, we show that exogenous administration of ELA peptide is able to increase invasiveness of extravillous trophoblasts in vitro, is able to change outgrowth morphology and reduce trophoblast proliferation ex vivo, and that these effects are, at least in part, independent of signaling through the Apelin Receptor (APLNR). Moreover, we show that circulating levels of ELA are highly variable between women, correlate with BMI, but are significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia. We conclude that the large variability and BMI dependence of ELA levels in circulation make this peptide an unlikely candidate to function as a first trimester preeclampsia screening biomarker, while in the future administering ELA or a derivative might be considered as a potential preeclampsia treatment option as ELA is able to drive extravillous trophoblast differentiation.

Highlights

The placenta orchestrates the normal growth and development of the fetus while serving as an interface with the maternal environment
In first trimester human placenta ELA and Apelin are expressed in villous cytotrophoblasts, syncytiotrophoblasts and in distal column extravillous trophoblasts, while their putative receptor Apelin Receptor (APLNR) is expressed in villous cytotrophoblasts and distal column extravillous trophoblasts (Fig. 1a)
We show that ELA and Apelin in the first trimester extravillous trophoblast cell line HTR8/SVneo are able to increase the invasive capacities of these cells and that this is, at least in part, independent from signaling through the APLNR as shown by lack of effect of treatment with APLNR antagonist ML221 or transfection of siRNAs directed against APLNR

Summary

Introduction

The placenta orchestrates the normal growth and development of the fetus while serving as an interface with the maternal environment. These cells originate from villous cytotrophoblasts and are able to undergo epithelial mesenchymal transition in which they differentiate from a proliferative to an invasive phenotype The latter cell type is responsible for remodeling of the maternal spiral arteries by infiltrating into the decidua and myometrium during the initial steps of placentation taking place in the first trimester of pregnancy. We investigate the expression of ELA in healthy and preeclamptic placental tissue, and its circulating levels in three different cohorts of healthy and preeclamptic pregnancies Using these cohorts we show that circulating levels of ELA are highly variable between women, correlate with BMI, but appear to be significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia

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