TGF-β3 Promotes Trophoblast Development in Sheep Embryos via ACSS2-Dependent Permissive Lipid Metabolism

  • Biol Reprod. 2025 Oct 1:ioaf220. doi: 10.1093/biolre/ioaf220.
Francesca Boffa  1 ,  Marika Domenicone  1 ,  Margherita Moncada  1 ,  Martina Lo Sterzo  1 ,  Luca Palazzese  1 ,  Aurora Scuderi  1 ,  Emanuele Capra  2 ,  Barbari Lazzari  2 ,  Luca Valbonetti  3 ,  Luisa Gioia  3 ,  Ramiro Alberio  4 ,  Domenico Iuso  1 ,  Pasqualino Loi  1 ,  Marta Czernik  1
Affiliations
  • 1. University of Teramo, Department of Veterinary Medicine, 64100 Teramo, Italy.
  • 2. CNR-IBBA, Institute of Agricultural Biology and Biotechnology, National Research Council, Via Einstein, Lodi 26900, Italy.
  • 3. Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, 64100, Italy.
  • 4. School of Biosciences, University of Nottingham, Sutton Bonington Campus, Nottingham, LE12 5RD, UK.
PMID: 41031631 DOI: 10.1093/biolre/ioaf220
Abstract

Transforming growth factor-beta (TGF-β) supports the in vitro maintenance of embryonic and trophoblast stem cells. Here, we demonstrated that, in a sheep embryo model, the transition from morula to blastocyst is positively regulated by TGF-β3, primarily through its promotion of trophoblast development. Our results indicate that morulae treated with TGF-β3 develop at a higher rate into blastocysts, characterized by an expanded trophoblast layer marked by CDX-2 expression. In blastocysts, TGF-β3 mediates transcriptional activation of genes involved in cell adhesion and lipid metabolism pathways, leading to remarkable in vitro outgrowth expansion and a substantial increase in trophoblast lipid droplet content. Functional analysis reveals that the positive effects of TGF-β3 are mitigated by inhibition of Acetyl-CoA synthetase Short-Chain Family Member 2 (ACSS2), a key enzyme upregulated by TGF-β3 and a promoter of de novo lipogenesis. These findings suggest that TGF-β3 modulates lipid metabolism during blastocyst formation and may play a potential role in regulating implantation and placental development.

Keywords
Blastocyst; In vitro; Ovine; TGF-β3; Trophoblast.
Products