{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:59:55Z","timestamp":1791197995705,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"55","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The human ovarian\u2010endometrial axis operates through coordinated, dynamic endocrine signaling that cannot be faithfully reproduced by static hormone supplementation. While endometrial organoids (EMOs) respond to exogenous estradiol and progesterone, whether a spatially organized human ovarian endocrine unit can instruct epithelial morphogenesis through physiologically integrated signaling remains unknown. Here, we engineered a multilayered human follicle\u2010like spheroid composed of primary granulosa cells and stromal\u2010derived theca\u2010like cells (SPHEGaT), recreating architectural and steroidogenic features of the ovarian follicle. These constructs generated sustained biologically active concentrations of estradiol and progesterone while maintaining high viability and low hypoxic burden. When co\u2010cultured with EMOs, SPHEGaTs induced progressive epithelial remodeling characterized by folding morphogenesis, increased progesterone receptor expression, and upregulation of secretory\/progesterone\u2010responsive genes including PAEP, SPP1 and HSD17B2. Strikingly, partial steroid depletion did not abolish organoid folding, whereas static supplementation with exogenous estradiol and progesterone failed to restore the differentiation phenotype. These findings suggest that endometrial remodeling is influenced not merely by hormone concentration, but also by additional signaling cues present within the SPHEGaT\u2010derived microenvironment. Together, this work establishes a human 3D platform in which integrated ovarian\u2010derived signaling supports epithelial morphogenesis, providing new framework for studying ovarian\u2010endometrial communication and highlighting the limitations of hormone\u2010only models in reproductive bioengineering.<\/jats:p>","DOI":"10.1002\/advs.76538","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:07:37Z","timestamp":1783606057000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatially Organized Human Ovarian Spheroids Instruct Endometrial Morphogenesis"],"prefix":"10.1002","volume":"13","author":[{"given":"Maria Jo\u00e3o","family":"Sousa","sequence":"first","affiliation":[{"name":"P\u00f4le de Recherche en Physiopathologie de la Reproduction Institut de Recherche Exp\u00e9rimentale et Clinique (IREC) Universit\u00e9 Catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke De","family":"Vriendt","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Plasticity in Health and Disease Cluster of Stem Cell and Developmental Biology Department of Development and Regeneration KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixian","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Plasticity in Health and Disease Cluster of Stem Cell and Developmental Biology Department of Development and Regeneration KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0544-8325","authenticated-orcid":false,"given":"Thalles Fernando Rocha","family":"Ruiz","sequence":"additional","affiliation":[{"name":"P\u00f4le de Recherche en Physiopathologie de la Reproduction Institut de Recherche Exp\u00e9rimentale et Clinique (IREC) Universit\u00e9 Catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Vankelecom","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Plasticity in Health and Disease Cluster of Stem Cell and Developmental Biology Department of Development and Regeneration KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1794-0368","authenticated-orcid":false,"given":"Christiani Andrade","family":"Amorim","sequence":"additional","affiliation":[{"name":"P\u00f4le de Recherche en Physiopathologie de la Reproduction Institut de Recherche Exp\u00e9rimentale et Clinique (IREC) Universit\u00e9 Catholique de Louvain  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010024\u201002651\u2010w"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/mi16101125"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2025.11.026"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.55241"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2008.08.067"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1268248"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153822"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14110829"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3516"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.148478"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010025\u201005807\u20105"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2013.07.004"},{"key":"e_1_2_11_14_1","volume-title":"Cell Microencapsulation: Methods and Protocols. 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