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In ruminants such as sheep, the LE orchestrates critical reproductive events, including noninvasive adhesion, conceptus elongation, and pregnancy recognition. However, existing models face significant limitations: conventional two-dimensional (2D) cultures fail to recapitulate endometrial complexity, while current organoid systems are predominantly derived from glandular epithelium.\u00a0Herein, we report the establishment of a robust three-dimensional (3D) culture system for generating ovine endometrial luminal epithelial organoids\u00a0using\u00a0an optimized expansion medium (ExM) supplemented with CHIR99021, Y-27632, SB202190, and the EphrinA1 ligand. The\u00a0resulting\u00a0organoids exhibited characteristic luminal epithelium features, including polarized architecture, mucin secretion, and high expression of lineage markers (keratin 18 (KRT-18), trophoblast cell surface antigen 2 (TROP2), and epithelial cell adhesion molecule (EpCAM)).\u00a0Moreover, we developed an apical-out polarity model that faithfully recapitulates the\u00a0in vivo\u00a0luminal orientation. Transcriptomic analysis confirmed the close resemblance between organoids and native luminal epithelium,\u00a0as well as\u00a0maintained hormonal responsiveness. Functional validation demonstrated the organoids\u2019 capacity to promote blastocyst expansion and trophoblast proliferation in co-culture systems,\u00a0as well as\u00a0substrate-specific adhesion\u00a0that was\u00a0enhanced by \u03b2-estradiol (E2)\u2009+\u2009medroxyprogesterone acetate (MPA) treatment.\u00a0Notably, we identified erythropoietin-producing hepatocellular receptor A (EphA) signaling as a novel regulator of stemness properties during organoid development. The\u00a0successful generation\u00a0of functional luminal epithelial organoids\u00a0thus\u00a0provides a physiologically relevant model that mirrors native endometrial structure, hormone responses, and embryo interactions.\u00a0As such, it\u00a0offers a valuable platform for investigating the mechanisms of endometrial receptivity and for screening potential therapeutics aimed at improving reproductive efficiency in ruminants.<\/jats:p>","DOI":"10.1186\/s13567-026-01764-4","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:03:33Z","timestamp":1780988613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and characterization of functional sheep endometrial luminal epithelial organoids"],"prefix":"10.1186","volume":"57","author":[{"given":"Jiahe","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxin","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingtian","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guomin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"1764_CR1","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1530\/JOE-10-0461","volume":"210","author":"M Singh","year":"2011","unstructured":"Singh M, Chaudhry P, Asselin E (2011) Bridging endometrial receptivity and implantation: network of hormones, cytokines, and growth factors. 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