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 (TGFβ) 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. TGFβ 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, TGFβ signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFβ 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 TGFβ 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 TGFβ superfamily, including TGFβs, 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 tgfβ’, ‘preeclampsia bmp’, ‘preeclampsia gdf’, ‘preeclampsia activin’, ‘endoglin preeclampsia’, ‘endoglin pregnancy’, ‘tgfβ signalling pregnancy’, ‘bmp signalling pregnancy’, ‘gdf signalling pregnancy’, ‘activin signalling pregnancy’, ‘Hofbauer cell tgfβ signalling’, ‘placental macrophages tgfβ’, ‘endothelial cells tgfβ’, ‘endothelium tgfβ signalling’, ‘trophoblast invasion tgfβ signalling’, ‘trophoblast invasion Smad’, ‘trophoblast invasion bmp’, ‘trophoblast invasion tgfβ’, ‘tgfβ preeclampsia’, ‘tgfβ placental development’, ‘TGFβ placental function’, ‘endothelial dysfunction preeclampsia tgfβ signalling’, ‘vascular remodelling placenta TGFβ’, ‘inflammation pregnancy tgfβ’, ‘immune response pregnancy tgfβ’, ‘immune tolerance pregnancy tgfβ’, ‘TGFβ pregnancy NK cells’, ‘bmp pregnancy NK cells’, ‘bmp pregnancy tregs’, ‘tgfβ pregnancy tregs’, ‘TGFβ placenta NK cells’, ‘TGFβ placenta tregs’, ‘NK cells preeclampsia’, ‘Tregs preeclampsia’. Only articles published in English until 2023 were used. OUTCOMES A comprehensive understanding of TGFβ 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, TGFβ ligands contribute to the proper functioning of a healthy maternal–foetal interface. However, dysregulation of TGFβ 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 TGFβ signalling. WIDER IMPLICATIONS The dysregulation of TGFβ 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 TGFβ 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.

中文翻译：

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TGFβ信号传导：整个怀孕期间炎症、胎盘健康和先兆子痫之间的联系


背景技术胎盘是生殖中独特且关键的器官，控制着确保成功妊娠的关键生长和细胞分化过程。胎盘发育是一个受到严格调控的动态过程，其中转化生长因子β（TGFβ）超家族发挥着核心作用。该多效性生长因子家族密切参与生殖生物学的各个方面的调节，特别是在妊娠前三个月的滋养层分化中。 TGFβ信号传导精确调节滋养层侵袭以及细胞从细胞滋养层向绒毛外滋养层的转变，这是一个上皮-间质转化样过程。在妊娠后期，TGFβ 信号传导确保胎盘内皮细胞中适当的血管化和血管生成。除了在滋养层和内皮细胞中的作用之外，TGFβ信号传导还通过促进半同种异体胎儿的母体耐受性来促进胎盘和蜕膜巨噬细胞的极化和功能。早期胎盘发育障碍与多种妊娠并发症有关，包括先兆子痫（PE），这是一种严重的并发症。新的证据表明 TGFβ 参与 PE 的发病机制，从而为人类胎盘干预提供了潜在的靶点。目的和基本原理这篇综合综述旨在探索和阐明 TGFβ 超家族主要成员的作用，包括 TGFβ、骨形态发生蛋白 (BMP)、激活素、抑制素、节点和生长分化因子 (GDF)。胎盘的发育和功能。 该综述的重点是在正常妊娠和整个妊娠期间并发 PE 的妊娠中，它们在胎盘主要细胞类型（即滋养层细胞、内皮细胞和免疫细胞）内的相互作用。检索方法 使用 PubMed 和 Google Scholar 进行文献检索，检索词：“TGF 信号传导先兆子痫”、“妊娠 TGF 信号传导”、“先兆子痫 tgfβ”、“先兆子痫 bmp”、“先兆子痫 gdf”、“先兆子痫激活素”、“内皮糖蛋白先兆子痫'、'内皮糖蛋白妊娠'、'tgfβ 信号怀孕'、'bmp 信号怀孕'、'gdf 信号怀孕'、'激活素信号怀孕'、'Hofbauer 细胞 tgfβ 信号'、'胎盘巨噬细胞 tgfβ'、'内皮细胞 tgfβ ', '内皮细胞 tgfβ 信号传导', '滋养层侵入 tgfβ 信号传导', '滋养层侵入 Smad', '滋养层侵入 bmp', '滋养层侵入 tgfβ', 'tgfβ 先兆子痫', 'tgfβ 胎盘发育', 'TGFβ 胎盘功能', '内皮功能障碍先兆子痫 tgfβ 信号传导'、'血管重塑胎盘 TGFβ'、'炎症妊娠 tgfβ'、'免疫反应妊娠 tgfβ'、'免疫耐受妊娠 tgfβ'、'TGFβ 妊娠 NK 细胞'、'bmp 妊娠 NK 细胞'、' bmp 妊娠 Tregs'、'tgfβ 妊娠 Tregs'、'TGFβ 胎盘 NK 细胞'、'TGFβ 胎盘 Tregs'、'NK 细胞先兆子痫'、'Tregs 先兆子痫'。仅使用 2023 年之前以英文发表的文章。结果 全面了解 TGFβ 信号传导及其在调节主要胎盘细胞类型相互关联的细胞功能中的作用，为了解妊娠期间胎盘成功发育和胎儿生长所必需的过程提供了宝贵的见解。 通过协调滋养层侵袭、血管化、免疫耐受和组织重塑，TGFβ配体有助于健康母胎界面的正常功能。然而，TGFβ信号传导失调与PE的发病机制有关，其中在PE中观察到的浅层滋养层侵袭、血管重塑缺陷、子宫胎盘灌注减少以及内皮细胞和免疫功能障碍都受到TGFβ信号传导改变的影响。更广泛的影响 PE 中 TGFβ 信号传导的失调对研究和临床实践具有重要意义。需要进一步研究以了解潜在的机制，包括不同配体的作用及其在病理生理条件下的调节，以发现新的治疗靶点。区分临床表现的 PE 亚型并全面研究不同胎盘细胞类型中的 TGFβ 信号传导是重要的第一步。为了将这些知识付诸实践，需要将临床前动物模型与新技术相结合。这也可能导致改进人类研究模型并确定潜在的治疗靶点，最终改善受影响妊娠的结果并减轻早泄的负担。