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

Transforming growth factor-beta (TGF-{beta}) 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-{beta}3, primarily through its promotion of trophoblast development. Our results indicate that morulae treated with TGF-{beta}3 develop at a higher rate into blastocysts, characterized by an expanded trophoblast layer marked by CDX-2 expression. In blastocysts, TGF-{beta}3 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 reveal that the positive effects of TGF-{beta}3 are mitigated by inhibition of Acetyl-CoA Synthetase Short-Chain Family Member 2 (ACSS2), a key enzyme upregulated by TGF-{beta}3 and a promoter of de novo lipgenensis. These findings suggest that TGF-{beta}3 modulates lipid metabolism during blastocyst formation and may play a potential role in regulating implantation and placental development.