Modulatory role of mTOR in trophoblast adaptive response in the early stage of placentation in sheep

in Reproduction
Authors:
I ViolaDepartment of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, Italy

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P ToschiDepartment of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, Italy

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I ManentiDepartment of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, Italy

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P AccorneroDepartment of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, Grugliasco, Italy

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M BarattaDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 11a, Parma, Italy

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Correspondence should be addressed to P TOSCHI; Email: paola.toschi@unito.it
DOI:
https://doi.org/10.1530/REP-22-0356
Volume/Issue:
Volume 165: Issue 3
Page Range:
313–324
Article Type:
Research Article
Online Publication Date:
25 Jan 2023
Copyright:
© Society for Reproduction and Fertility 2023
Restricted access

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In brief

Fibroblast growth factor-2 (FGF2) is essential for early placenta development in sheep. This study shows that the mechanistic target of rapamycin is the key modulator of trophoblast adaptive response under FGF2 modulation.

Abstract

During the early stage of placentation in sheep, normal conceptus development is affected by trophoblast cell functionality, whose dysregulation results in early pregnancy loss. Trophoblast metabolism is supported mainly by histotrophic factors, including fibroblast growth factor-2 (FGF2), which are involved in cell differentiation and function through the modulation of specific cellular mechanisms. The mechanistic target of rapamycin (mTOR) is known as a cellular ‘nutrient sensor’, but its downstream regulation remains poorly understood. The hypothesis was that during trophoblast development, the FGF2 effect is mediated by mTOR signalling pathway modulation. Primary trophoblast cells from 21-day-old sheep placenta were characterised and subjected to FGF2 and rapamycin treatment to study the effects on cell functionality and gene and protein expression profiles. The model showed mainly mononuclear cells with epithelial cell-like growth and placental morphological properties, expressing typical trophoblast markers. FGF2 promoted cell proliferation and migration under normal culture conditions, whereas mTOR inhibition reversed this effect. When the mTOR signalling pathway was activated, FGF2 failed to influence invasion activity. mTOR inhibition significantly reduced cell motility, but FGF2 supplementation restored motility even when mTOR was inhibited. Interestingly, mTOR inhibition influenced endocrine trophoblast marker regulation. Although FGF2 supplementation did not affect ovine placenta lactogen expression, as observed in the control, interferon-tau was drastically reduced. This study provides new insights into the mechanism underlying mTOR inhibitory effects on trophoblast cell functionality. In addition, as mTOR is involved in the expression of hormonal trophoblast markers, it may play a crucial role in early placenta growth and fetal–maternal crosstalk.

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Sept 2018 onwards Past Year Past 30 Days
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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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