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TCF7L2 is expressed in human placental tissues and EVTs and regulates EVT motility, but its trophoblast targets and early differentiation mechanism remain unclear. Using trophoblast stem cells (TSCs), expression of TCF7L2 rises during EVT formation. Loss of TCF7L2 impairs TSC proliferation and blocks EVT formation, whereas overexpression inhibits TSC differentiation into syncytiotrophoblasts (STs), identifies context-specific gene regulation.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/tcf7l2-is-essential-for-the-differentiation-and-invasive-function-of-human-extravillous-trophoblast/450385/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/tcf7l2-is-essential-for-the-differentiation-and-invasive-function-of-human-extravillous-trophoblast/450385.png","ImageObject",300,407,{"name":92,"@type":93},"\tJames","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-05","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What key roles do extravillous trophoblasts (EVTs) play in placental development?","Question",{"text":112,"@type":113},"EVTs anchor the placenta, invade the maternal decidua, and remodel maternal spiral arteries to establish appropriate blood flow and nutrient/oxygen delivery.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does altering TCF7L2 affect trophoblast stem cell differentiation and EVT formation?",{"text":117,"@type":113},"Loss-of-function studies show TCF7L2 is required for TSC proliferation and essential for EVT formation. In contrast, overexpression of TCF7L2 blocks TSC differentiation into syncytiotrophoblasts (STs).",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links TCF7L2 to EVT formation in trophoblasts?",{"text":121,"@type":113},"Genome-wide binding and integrative gene expression analyses indicate that TCF7L2 promotes EVT formation by directly activating extracellular matrix organization while suppressing cell-cycle–associated genes, and it also collaborates with other EVT factors.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},450385,1790794650,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},2336474466412,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Cellular and Molecular Life Sciences (2026) 83:30  \n[https://doi.org/10.1007/s00018-025-05991-4](https://doi.org/10.1007/s00018-025-05991-4) Cellular and Molecular Life Sciences  \nORIGINAL ARTICLE  \nTCF7L2 is essential for the differentiation and invasive function of human extravillous trophoblast  \nEnoch Appiah Adu-Gyamfi1 · Joudi Salamah1 · Elisha Cheeran1 · Brandt Beck1 · Zaineb Ahmad1 · Bum-Kyu Lee1  \nReceived: 20 February 2025 / Revised: 29 October 2025 / Accepted: 10 November 2025 © The Author(s) 2025, modified publication 2026  \nAbstract  \nExtravillous trophoblasts (EVTs) play essential roles in placental development by anchoring the placenta, invading the maternal decidua, and remodeling spiral arteries. TCF7L2 is known to be expressed in human placental tissues and EVTs, and it controls EVT motility. However, the targets of TCF7L2 in trophoblasts and the mechanism by which it contributes to early trophoblast differentiation are largely unknown. Here, using trophoblast stem cells (TSCs), we investigate the expression patterns of TCF7L2 during trophoblast lineage differentiation, revealing that its expression gradually elevates throughout EVT formation. Loss-of-function studies uncover that TCF7L2 is implicated in the proliferation of TSCs and is essential for EVT formation. Conversely, overexpression of TCF7L2 hinders TSC differentiation into STs. We identify TCF7L2 binding sites across the genome in TSCs and EVTs. Integrative analyses of TCF7L2 targets with global gene expression profiles unveil that TCF7L2 facilitates EVT formation by directly activating extracellular matrix organization while suppressing genes linked to the cell cycle. Moreover, overlap analyses of TCF7L2 targets with those of other EVT factors reveal that TCF7L2 collaborates with other EVT factors to promote EVT formation. In summary, our findings highlight context-specific functions of TCF7L2 in the trophoblast lineage.  \nKeywords Trophoblast stem cells · Placental development · TCF7L2 transcription factor · Trophoblast lineage differentiation · Extravillous trophoblast  \nAbbreviations  \nTSCs Trophoblast stem cells  \nCTs Cytotrophoblasts (CTs)  \nSTs Syncytiotrophoblasts  \nEVTs Extravillous trophoblasts IUGR Intrauterine growth restriction PE Preeclampsia  \nTCF7L2 Transcription factor-7-like-2 GDM Gestational diabetes mellitus  \n􀀍 Bum-Kyu Lee [blee6@albany.edu](blee6@albany.edu)  \n1 Department of Biomedical Sciences, Cancer Research Center, College of Integrated Health Sciences, University at Albany, State University of New York, Rensselaer, NY 12222, USA  \nIntroduction  \nThe placenta is a vital organ that facilitates nutrient and gas exchange between the mother and the developing fetus, supports hormonal regulation, and ensures immunological protection [1] . During early placental development, trophectodermal cells, which originate from the outermost epithelial layer of the blastocyst, give rise to diverse trophoblast cell types: cytotrophoblasts (CTs), syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs) [2] . EVT-mediated remodeling of the uterine spiral arteries is fundamental for establishing the blood flow between themother and the placenta [3] . EVTs invade maternal uterine tissue, remodel maternal spiral arteries into large-diameter vessels, and establish low-pressure blood flow to the placenta, ensuring constant nutrient and oxygen delivery [4] . Accumulating evidence suggests that defects in this process, such as insufficient invasion of decidual tissue or incomplete transformation of spiral arteries, can lead to the pathogenesis of obstetrical complications, including stillbirth, intrauterine growth restriction (IUGR), and preeclampsia  \n1 3  \n(PE) [5–7]. Therefore, proper differentiation of trophoblasts into EVTs is crucial for a healthy pregnancy.  \nTranscription factor-7-like-2 (TCF7L2), also known as T-cell factor 4 (TCF4), is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family, which includes LEF1, TC","cbCaiiwsqfFW67Qj","https://ap.wps.com/l/cbCaiiwsqfFW67Qj","pdf",3630143,17,"English","# Abstract\n# Keywords\n# Abbreviations\n# Introduction","[{\"question\":\"What key roles do extravillous trophoblasts (EVTs) play in placental development?\",\"answer\":\"EVTs anchor the placenta, invade the maternal decidua, and remodel maternal spiral arteries to establish appropriate blood flow and nutrient/oxygen delivery.\"},{\"question\":\"How does altering TCF7L2 affect trophoblast stem cell differentiation and EVT formation?\",\"answer\":\"Loss-of-function studies show TCF7L2 is required for TSC proliferation and essential for EVT formation. In contrast, overexpression of TCF7L2 blocks TSC differentiation into syncytiotrophoblasts (STs).\"},{\"question\":\"What mechanism links TCF7L2 to EVT formation in trophoblasts?\",\"answer\":\"Genome-wide binding and integrative gene expression analyses indicate that TCF7L2 promotes EVT formation by directly activating extracellular matrix organization while suppressing cell-cycle–associated genes, and it also collaborates with other EVT factors.\"}]","TCF7L2 is essential for the differentiation and invasive function of human extravillous trophoblast | PDF",1790733044,43]