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：整个妊娠期间炎症、胎盘健康和子痫前期之间的联系


背景 胎盘是生殖中独特而关键的器官，控制着关键的生长和细胞分化过程，确保成功怀孕。胎盘发育是一个严格调节的动态过程，其中转化生长因子 β （TGFβ） 超家族起着核心作用。这个多效性生长因子家族深度参与调节生殖生物学的各个方面，特别是在怀孕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和细胞从细胞滋养层细胞向绒毛外滋养层的转变，这是一个上皮到间充质转化样过程。在怀孕后期，TGFβ 信号传导确保胎盘内皮细胞中适当的血管形成和血管生成。除了在滋养层细胞和内皮细胞中的作用外，TGFβ 信号传导还通过促进母体对半同种异体胎儿的耐受性，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，包括子痫前期 （PE），这是严重的并发症之一。新出现的证据表明，TGFβ 参与 PE 的发病机制，因此为干预人胎盘提供了潜在的靶点。客观和基本原理本综述旨在探讨和阐明 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、结节和生长分化因子 （GDF），在胎盘发育和功能中的作用。 本综述的重点是它们在胎盘主要细胞类型（即滋养层、内皮细胞和免疫细胞）中的相互作用，包括正常妊娠和整个妊娠期间并发 PE 的妊娠。检索方法 使用 PubMed 和 Google Scholar 进行文献检索，检索词： 'TGF 信号传导子痫前期'， '妊娠 TGF 信号传导'， '子痫前期 tgfβ'， '子痫前期 bmp'， '子痫前期 gdf'， '子痫前期激活素'， '内皮糖蛋白子痫前期'， '内胚素妊娠'， 'tgfβ 信号妊娠'， 'BMP 妊娠信号'， 'GDF 信号妊娠'， '激活素信号妊娠'， '霍夫鲍尔细胞 tgfβ 信号'， '胎盘巨噬细胞 tgfβ'， '内皮细胞 tgfβ'， '内皮TGFβ信号'， '滋养层侵袭TGFβ信号'， '滋养层侵袭Smad'， '滋养层侵袭BMP'， '滋养层侵袭TGFβ'， 'TGFβ子痫前期'， 'TGFβ胎盘发育'， 'TGFβ胎盘功能'， '子痫前期内皮功能障碍TGFβ信号转导'， '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妊娠妊娠Tregs'， 'TGFβ 妊娠 Tregs'， 'TGFβ 胎盘 NK 细胞'， 'TGFβ 胎盘 Tregs'， 'NK 细胞子痫前期'， 'Tregs 子痫前期'。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互连细胞功能中的作用，为了解怀孕期间胎盘成功发育和胎儿生长所必需的过程提供了有价值的见解。 通过协调滋养层侵袭、血管形成、免疫耐受和组织重塑，TGFβ 配体有助于健康母胎界面的正常运作。然而，TGFβ 信号的失调与 PE 的发病机制有关，其中浅滋养层浸润、血管重塑缺陷、子宫胎盘灌注减少以及在 PE 中观察到的内皮细胞和免疫功能障碍，都受到 TGFβ 信号改变的影响。更广泛的影响 PE 中 TGFβ 信号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，需要结合新技术的临床前动物模型。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局并减轻 PE 的负担。