Roles of TGF-β Superfamily Proteins in Extravillous Trophoblast Invasion.

Following embryo implantation, extravillous trophoblasts (EVTs) invade the maternal decidua to a certain extent during early pregnancy, which is critical for normal placentation and successful pregnancy in humans. Although sharing a similar protein structure, the transforming growth factor-β (TGF-β) superfamily members exert divergent functions in regulating EVT invasion, which contributes to a relative balance of TGF-β superfamily proteins in precisely modulating this process at the maternal-fetal interface during the first trimester of pregnancy. This review details recent advances in our understanding of the functions of TGF-β superfamily members and their corresponding receptors, signaling pathways, and downstream molecular targets in regulating human EVT invasion from studies using various in vitro or ex vivo experimental models. Also, the relevance of these discoveries about TGF-β superfamily members to adverse pregnancy outcomes is summarized. The application of 3D culture trophoblast organoids, single-cell sequencing, and microfluidic assays in EVT invasion studies will help better reveal the molecular mechanisms through which TGF-β superfamily members regulate human EVT invasion, shedding light on the development of innovative strategies for predicting, diagnosing, treating, and preventing adverse human pregnancy outcomes related to EVT invasion dysfunction.