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Their secretions are vital for endometrial functions and early pregnancy, yet the mechanisms controlling gland development are not well understood. Although various 3D endometrial models exist, none fully replicate human gland development in vitro. This study establishes a robust 3D endometrial assembloid model by integrating human endometrial organoids (EOs) and human endometrial stromal cells (HESCs), successfully replicating tubular gland formation and illustrating essential stromal\u2010epithelial interactions. Transcriptomic analyses identify Wnt Family Member 7B (WNT7B) as an intrinsic inhibitor of gland formation and development, regulated extrinsically by transforming growth factor beta\u20101 (TGF\u03b21) signaling through vitamin D receptor (VDR) interactions between EOs and HESCs. Endometrium\u2010specific WNT7B knockout mice exhibit enhanced gland development further supports WNT7B's inhibitory role in endometrial gland development. Estradiol facilitates tubular gland formation by suppressing WNT7B expression in vitro, which is confirmed in estradiol\u2010stimulated mouse models and clinical samples from women undergoing ovarian stimulation for in vitro fertilization. These findings elucidate the central roles of estradiol\u2010WNT7B signaling and stromal\u2010derived TGF\u03b21\u2010VDR crosstalk in endometrial gland development, providing a foundation for improved 3D endometrial models and identifying therapeutic targets for gland\u2010related disorders like endometriosis, infertility, and endometrial hyperplasia.<\/jats:p>","DOI":"10.1002\/advs.202509664","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T06:13:48Z","timestamp":1766470428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Endometrial Assembloid Model Reveals Endometrial Gland Development Regulation by Estradiol\u2010Driven\n                    <i>WNT7B<\/i>\n                    Suppression"],"prefix":"10.1002","volume":"13","author":[{"given":"Xintong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"},{"name":"Department of Health Technology and Informatics The Hong Kong Polytechnic University  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leqian","family":"Lin","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Fertility Regulation The University of Hong Kong \u2013 Shenzhen Hospital  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi Kit Matthew","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Fertility Regulation The University of Hong Kong \u2013 Shenzhen Hospital  Shenzhen China"},{"name":"School of Biomedical Sciences The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai\u2010Fai","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka\u2010Wang","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology The University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest H. 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