PMID- 36602917
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20230328
IS  - 1741-7899 (Electronic)
IS  - 1470-1626 (Linking)
VI  - 165
IP  - 3
DP  - 2023 Mar 1
TI  - Modulatory role of mTOR in trophoblast adaptive response in the early stage of 
      placentation in sheep.
PG  - 313-324
LID - 10.1530/REP-22-0356 [doi]
AB  - 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.
FAU - Viola, I
AU  - Viola I
AUID- ORCID: 0000-0002-4268-5613
AD  - Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 
      Grugliasco, Italy.
FAU - Toschi, P
AU  - Toschi P
AUID- ORCID: 0000-0003-0963-7254
AD  - Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 
      Grugliasco, Italy.
FAU - Manenti, I
AU  - Manenti I
AD  - Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 
      Grugliasco, Italy.
FAU - Accornero, P
AU  - Accornero P
AD  - Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, 
      Grugliasco, Italy.
FAU - Baratta, M
AU  - Baratta M
AD  - Department of Chemistry, Life Sciences and Environmental Sustainability, 
      University of Parma, Parco Area delle Scienze 11a, Parma, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230125
PL  - England
TA  - Reproduction
JT  - Reproduction (Cambridge, England)
JID - 100966036
RN  - 103107-01-3 (Fibroblast Growth Factor 2)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Pregnancy
MH  - Animals
MH  - Sheep
MH  - Female
MH  - *Trophoblasts/metabolism
MH  - *Placentation
MH  - Placenta/metabolism
MH  - Fibroblast Growth Factor 2/metabolism
MH  - Sirolimus/pharmacology/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
EDAT- 2023/01/06 06:00
MHDA- 2023/01/27 06:00
CRDT- 2023/01/05 12:52
PHST- 2022/10/03 00:00 [received]
PHST- 2023/01/05 00:00 [accepted]
PHST- 2023/01/06 06:00 [pubmed]
PHST- 2023/01/27 06:00 [medline]
PHST- 2023/01/05 12:52 [entrez]
AID - 10.1530/REP-22-0356 [doi]
PST - epublish
SO  - Reproduction. 2023 Jan 25;165(3):313-324. doi: 10.1530/REP-22-0356. Print 2023 
      Mar 1.