PDF(Pubmed)
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 (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: 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.
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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：胎盘是生殖过程中一个独特而关键的器官，控制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控的动态过程,其中转化生长因子β(TGFβ)超家族起着核心作用。这个家族的多效性生长因子主要参与调节生殖生物学的各个方面，特别是在妊娠前三个月的滋养细胞分化中。TGFβ信号精确调节滋养层细胞侵袭和细胞滋养层向绒毛外滋养层细胞的转变，这是一个上皮到间质转化的过程。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。除了它在滋养细胞和内皮细胞中的作用，TGFβ信号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。早期胎盘发育的紊乱与几种妊娠并发症有关。包括子痫前期（PE），这是严重的并发症之一。新的证据表明TGFβ参与了PE的发病机制。从而为人类胎盘的干预提供了潜在的目标。
目的：本综述旨在探讨和阐明TGFβ超家族主要成员的作用，包括TGFβs，骨形态发生蛋白（BMPs），活化素,抑制蛋白,节点,和生长分化因子(GDF)，在胎盘发育和功能的背景下。该综述集中于它们在胎盘主要细胞类型内的相互作用，即滋养细胞，内皮细胞，和免疫细胞，在正常妊娠和妊娠合并PE在整个怀孕期间。
方法：使用PubMed和GoogleScholar进行了文献检索，搜索词：\'TGF-β信号先兆子痫\'，\'妊娠TGF信号\'，\'子痫前期tgfβ\'，\'子痫前期bmp\',\'先兆子痫gdf\',\'子痫前期激活素\',\'endoglin先兆子痫\',\'endoglin怀孕\',\'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tgfβ信号”，\'滋养细胞入侵tgfβ信号\'，\'滋养细胞入侵Smad\',\'滋养层侵入bmp\',\'滋养层入侵tgfβ\'，\'tgfβ子痫前期\'，\'tgfβ胎盘发育\'，\'TGFβ胎盘功能\',“内皮功能障碍先兆子痫tgfβ信号”，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怀孕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信号及其在调节主要胎盘细胞类型的相互联系的细胞功能中的作用，为妊娠期间成功胎盘发育和胎儿生长所必需的过程提供了有价值的见解。通过策划滋养细胞入侵，血管化,免疫耐受，和组织重塑，TGFβ配体有助于健康的母胎界面的正常功能。然而,TGFβ信号的失调与PE的发病机理有关，浅层滋养细胞入侵的地方，有缺陷的血管重建,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，都受到改变的TGFβ信号传导的影响。
结论：PE中TGFβ信号的失调对研究和临床实践具有重要意义。需要进一步调查以了解潜在的机制，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PE的临床表现亚型和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。这也可能导致改进的人类研究模型和确定潜在的治疗目标，最终改善受影响妊娠的结局并减轻PE的负担。
目的：本综述旨在探讨和阐明TGFβ超家族主要成员的作用，包括TGFβs，骨形态发生蛋白（BMPs），活化素,抑制蛋白,节点,和生长分化因子(GDF)，在胎盘发育和功能的背景下。该综述集中于它们在胎盘主要细胞类型内的相互作用，即滋养细胞，内皮细胞，和免疫细胞，在正常妊娠和妊娠合并PE在整个怀孕期间。
方法：使用PubMed和GoogleScholar进行了文献检索，搜索词：\'TGF-β信号先兆子痫\'，\'妊娠TGF信号\'，\'子痫前期tgfβ\'，\'子痫前期bmp\',\'先兆子痫gdf\',\'子痫前期激活素\',\'endoglin先兆子痫\',\'endoglin怀孕\',\'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tgfβ信号”，\'滋养细胞入侵tgfβ信号\'，\'滋养细胞入侵Smad\',\'滋养层侵入bmp\',\'滋养层入侵tgfβ\'，\'tgfβ子痫前期\'，\'tgfβ胎盘发育\'，\'TGFβ胎盘功能\',“内皮功能障碍先兆子痫tgfβ信号”，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怀孕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信号及其在调节主要胎盘细胞类型的相互联系的细胞功能中的作用，为妊娠期间成功胎盘发育和胎儿生长所必需的过程提供了有价值的见解。通过策划滋养细胞入侵，血管化,免疫耐受，和组织重塑，TGFβ配体有助于健康的母胎界面的正常功能。然而,TGFβ信号的失调与PE的发病机理有关，浅层滋养细胞入侵的地方，有缺陷的血管重建,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，都受到改变的TGFβ信号传导的影响。
结论：PE中TGFβ信号的失调对研究和临床实践具有重要意义。需要进一步调查以了解潜在的机制，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PE的临床表现亚型和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。这也可能导致改进的人类研究模型和确定潜在的治疗目标，最终改善受影响妊娠的结局并减轻PE的负担。
