TGFb signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy

Abstract

BACKGROUND: The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFb) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFb signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFb signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFb signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFb is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE: This comprehensive review aims to explore and elucidate the roles of the major members of the TGFb superfamily, including TGFbs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS: A literature search was carried out using PubMed and Google Scholar, searching terms: ‘TGF signalling preeclampsia’, ‘pregnancy TGF signalling’, ‘preeclampsia tgfb’, ‘preeclampsia bmp’, ‘preeclampsia gdf’, ‘preeclampsia activin’, ‘endoglin preeclampsia’, ‘endoglin pregnancy’, ‘tgfb signalling pregnancy’, ‘bmp signalling pregnancy’, ‘gdf signalling pregnancy’, ‘activin signalling pregnancy’, ‘Hofbauer cell tgfb signalling’, ‘placental macrophages tgfb’, ‘endothelial cells tgfb’, ‘endothelium tgfb signalling’, ‘trophoblast invasion tgfb signalling’, ‘trophoblast invasion Smad’, ‘trophoblast invasion bmp’, ‘trophoblast invasion tgfb’, ‘tgfb preeclampsia’, ‘tgfb placental development’, ‘TGFb placental function’, ‘endothelial dysfunction preeclampsia tgfb signalling’, ‘vascular remodelling placenta TGFb’, ‘inflammation pregnancy tgfb’, ‘immune response pregnancy tgfb’, ‘immune tolerance pregnancy tgfb’, ‘TGFb pregnancy NK cells’, ‘bmp pregnancy NK cells’, ‘bmp pregnancy tregs’, ‘tgfb pregnancy tregs’, ‘TGFb placenta NK cells’, ‘TGFb placenta tregs’, ‘NK cells preeclampsia’, ‘Tregs preeclampsia’. Only articles published in English until 2023 were used. OUTCOMES: A comprehensive understanding of TGFb signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFb ligands contribute to the proper functioning of a healthy maternal–foetal interface. However, dysregulation of TGFb signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFb signalling. WIDER IMPLICATIONS: The dysregulation of TGFb signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFb signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE.