Roles of TGF-β Superfamily Proteins in Extravillous Trophoblast Invasion

Ongoing clinical and basic research efforts are deepening our understanding about how transforming growth factor-β (TGF-β) superfamily members modulate human extravillous trophoblast (EVT) invasion. A present lack of suitable in vivo research models, coupled to the frequent use of supraphysiological doses during in vitro and ex vivo functional studies, has limited informative interpretations about how diverse biomolecular networks regulate human EVT invasion. The development of advanced technologies, including high-throughput sequencing, 3D organoid cultures, and microfluidic assays, as well as studies focusing on additional tiers of biological regulation (e.g., epigenetic modifications), is collectively unveiling a deeper understanding of TGF-β superfamily function in human EVT invasion. Such basic insights are now enabling an era of drug-based interventions, including use of TGF-β signaling agonists and antagonists as well as therapeutic use of the TGF-β superfamily proteins themselves as protein drugs, for the diagnosis and treatment of pregnancy disorders related to disrupted EVT 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. 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. primary trophoblast cells/human trophoblast stem cells are collected and cultured in 3D, which are embedded within an extracellular matrix hydrogel matrix such as Matrigel. These ex vivo model systems developed in 2018 better mimic the physiological context of human biology than do cells grown on flat 2D surfaces. organs or small pieces of tissue that are removed and cultured in vitro in the laboratory. This ex vivo model requires a highly maintained environment in order to recreate original cellular conditions. a subset of trophoblasts that originated at the tip of the anchoring villi and have subsequently migrated beyond the confines of the villous trees. EVTs are essential for anchoring fetuses to maternal uteruses and for the remodeling of uterine spiral arteries. health problems that occur during or after pregnancy that can adversely influence maternal and/or fetal health, including miscarriage, pre-eclampsia, intrauterine growth restrictions, and gestational diabetes, among others. growth factors that share a similar protein structure with a cysteine knot and function in reproductive processes through their actions associated with cell migration, proliferation, apoptosis, differentiation, and tissue remodeling.