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

BOFFA, F.; Moncada, M.; Lo Sterzo, M.; Palazzese, L.; Scudieri, A.; Domenicone, M.; Capra, E.; Lazzari, B.; Gioia, L.; Alberio, R.; Iuso, D.; Loi, P.; Czernik, M.

doi:10.1101/2025.01.02.631122

bioRxiv · 10.1101/2025.01.02.631122

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

BOFFA, F.·Moncada, M.·Lo Sterzo, M.·Palazzese, L.·Scudieri, A.·Domenicone, M.·Capra, E.·Lazzari, B.·Gioia, L.·Alberio, R.·Iuso, D.·Loi, P.·Czernik, M.

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Abstract

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.

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BOFFA, F., Moncada, M., Lo Sterzo, M., Palazzese, L., Scudieri, A., Domenicone, M., Capra, E., Lazzari, B., Gioia, L., Alberio, R., Iuso, D., Loi, P., Czernik, M.. 2025-01-02. TGF-β3 Promotes Trophoblast Development via ACSS2-Dependent Permissive Lipid Metabolism. https://doi.org/10.1101/2025.01.02.631122

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