{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T20:02:57Z","timestamp":1792526577730,"version":"4.5.0"},"reference-count":297,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Program Inflammatory Disorders in Pregnancy"},{"name":"Medical University of Graz, Austria"},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund FWF","doi-asserted-by":"crossref","award":["T1029-B26"],"award-info":[{"award-number":["T1029-B26"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 La Marat\u00f3 de TV3","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,1]]},"abstract":"Abstract<\/jats:title>\n \n BACKGROUND<\/jats:title>\n 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 (TGF\u03b2) 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. TGF\u03b2 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, TGF\u03b2 signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGF\u03b2 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 TGF\u03b2 is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta.<\/jats:p>\n <\/jats:sec>\n \n OBJECTIVE AND RATIONALE<\/jats:title>\n This comprehensive review aims to explore and elucidate the roles of the major members of the TGF\u03b2 superfamily, including TGF\u03b2s, 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.<\/jats:p>\n <\/jats:sec>\n \n SEARCH METHODS<\/jats:title>\n A literature search was carried out using PubMed and Google Scholar, searching terms: \u2018TGF signalling preeclampsia\u2019, \u2018pregnancy TGF signalling\u2019, \u2018preeclampsia tgf\u03b2\u2019, \u2018preeclampsia bmp\u2019, \u2018preeclampsia gdf\u2019, \u2018preeclampsia activin\u2019, \u2018endoglin preeclampsia\u2019, \u2018endoglin pregnancy\u2019, \u2018tgf\u03b2 signalling pregnancy\u2019, \u2018bmp signalling pregnancy\u2019, \u2018gdf signalling pregnancy\u2019, \u2018activin signalling pregnancy\u2019, \u2018Hofbauer cell tgf\u03b2 signalling\u2019, \u2018placental macrophages tgf\u03b2\u2019, \u2018endothelial cells tgf\u03b2\u2019, \u2018endothelium tgf\u03b2 signalling\u2019, \u2018trophoblast invasion tgf\u03b2 signalling\u2019, \u2018trophoblast invasion Smad\u2019, \u2018trophoblast invasion bmp\u2019, \u2018trophoblast invasion tgf\u03b2\u2019, \u2018tgf\u03b2 preeclampsia\u2019, \u2018tgf\u03b2 placental development\u2019, \u2018TGF\u03b2 placental function\u2019, \u2018endothelial dysfunction preeclampsia tgf\u03b2 signalling\u2019, \u2018vascular remodelling placenta TGF\u03b2\u2019, \u2018inflammation pregnancy tgf\u03b2\u2019, \u2018immune response pregnancy tgf\u03b2\u2019, \u2018immune tolerance pregnancy tgf\u03b2\u2019, \u2018TGF\u03b2 pregnancy NK cells\u2019, \u2018bmp pregnancy NK cells\u2019, \u2018bmp pregnancy tregs\u2019, \u2018tgf\u03b2 pregnancy tregs\u2019, \u2018TGF\u03b2 placenta NK cells\u2019, \u2018TGF\u03b2 placenta tregs\u2019, \u2018NK cells preeclampsia\u2019, \u2018Tregs preeclampsia\u2019. Only articles published in English until 2023 were used.<\/jats:p>\n <\/jats:sec>\n \n OUTCOMES<\/jats:title>\n A comprehensive understanding of TGF\u03b2 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, TGF\u03b2 ligands contribute to the proper functioning of a healthy maternal\u2013foetal interface. However, dysregulation of TGF\u03b2 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 TGF\u03b2 signalling.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS<\/jats:title>\n The dysregulation of TGF\u03b2 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 TGF\u03b2 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humupd\/dmae007","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T09:58:29Z","timestamp":1709114309000},"page":"442-471","source":"Crossref","is-referenced-by-count":72,"title":["TGF\u03b2 signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy"],"prefix":"10.1093","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9440-9250","authenticated-orcid":false,"given":"Monika","family":"Horvat Mercnik","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Medical University of Graz , Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7523-670X","authenticated-orcid":false,"given":"Carolin","family":"Schliefsteiner","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Medical University of Graz , Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3205-0710","authenticated-orcid":false,"given":"Gonzalo","family":"Sanchez-Duffhues","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Tissue-Specific BMP Signalling ISPA-HUCA , Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5589-8642","authenticated-orcid":false,"given":"Christian","family":"Wadsack","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Medical University of Graz , Graz, Austria"},{"name":"BioTechMed-Graz , Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,22]]},"reference":[{"key":"2024070106512566300_dmae007-B1","doi-asserted-by":"crossref","first-page":"27678","DOI":"10.1074\/jbc.272.44.27678","article-title":"T\u03b2RI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling","volume":"272","author":"Abdollah","year":"1997","journal-title":"J Biol Chem"},{"key":"2024070106512566300_dmae007-B2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2016.12.007","article-title":"HTR-8\/SVneo cell line contains a mixed population of cells","volume":"50","author":"Abou-Kheir","year":"2017","journal-title":"Placenta"},{"key":"2024070106512566300_dmae007-B3","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/biolre\/ioz186","article-title":"Regulation of placentation by the transforming growth factor beta superfamily","volume":"102","author":"Adu-Gyamfi","year":"2020","journal-title":"Biol Reprod"},{"key":"2024070106512566300_dmae007-B4","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/aji.12288","article-title":"Trophoblast induces monocyte differentiation into CD14+\/CD16+ macrophages","volume":"72","author":"Aldo","year":"2014","journal-title":"Am J Reprod Immunol"},{"key":"2024070106512566300_dmae007-B5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.placenta.2014.02.004","article-title":"Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells","volume":"35","author":"Alijotas-Reig","year":"2014","journal-title":"Placenta"},{"key":"2024070106512566300_dmae007-B6","doi-asserted-by":"crossref","first-page":"E1212","DOI":"10.1073\/pnas.1303094110","article-title":"Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4","volume":"110","author":"Amita","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024070106512566300_dmae007-B7","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.3389\/fimmu.2020.01864","article-title":"Mechanisms of key innate immune cells in early- and late-onset preeclampsia","volume":"11","author":"Aneman","year":"2020","journal-title":"Front Immunol"},{"key":"2024070106512566300_dmae007-B8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41586-023-05869-0","article-title":"Spatial multiomics map of trophoblast development in early pregnancy","volume":"616","author":"Arutyunyan","year":"2023","journal-title":"Nature"},{"key":"2024070106512566300_dmae007-B9","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1016\/S0021-9258(18)32345-7","article-title":"Transforming growth factor-beta in human platelets. 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