{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:51:11Z","timestamp":1791514271633,"version":"4.3.4"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":87,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Postdoctoral Fellowship Program of CPSF","award":["GZC20233157"],"award-info":[{"award-number":["GZC20233157"]}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2022JJ40779"],"award-info":[{"award-number":["2022JJ40779"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2023JJ40956"],"award-info":[{"award-number":["2023JJ40956"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301835"],"award-info":[{"award-number":["82301835"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371682"],"award-info":[{"award-number":["82371682"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science Foundation For Excellent Young Scholars of Hunan Province","award":["2024JJ4091"],"award-info":[{"award-number":["2024JJ4091"]}]},{"name":"Youth Fund of Xiangya Hospital","award":["2021Q03"],"award-info":[{"award-number":["2021Q03"]}]},{"name":"key research and development plan of Hunan Province","award":["2021SK2028"],"award-info":[{"award-number":["2021SK2028"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Endometrial organoids, with their three-dimensional structure and robust hormonal responsiveness, have emerged as valuable models for investigating uterine physiology and embryo implantation. However, conventional derivation from endometrial biopsies is invasive, carries surgical risks, and limits repeated sampling. This study introduces uterine lavage fluid as a non-invasive source for generating endometrial organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established endometrial organoids from uterine lavage fluid (UF-EOs) and compared them with matched tissue-derived endometrial organoids (T-EOs) for morphology, proliferation, epithelial marker expression, transcriptomic profiles, and hormone responsiveness. Lavage fluid was collected from reproductive-age women with normal endometrium and from patients with intrauterine adhesions (IUA). Differential gene-expression analysis between IUA-derived and control organoids was performed to identify IUA-associated signatures. A microinjection platform was developed to deliver HTR8\/SVneo trophoblast spheroids into the organoid lumen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      UF-EOs were successfully derived from 90% of control individuals (9\/10) and 60% of IUA patients (6\/10). UF-EOs and T-EOs were morphologically indistinguishable, with comparable proliferation rates (104.6\u2009\u00b1\u20096.21 versus 106.4\u2009\u00b1\u20095.16;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&gt;\u20090.05) and equivalent expression of epithelial markers (EpCAM, Cytokeratin 7, E-cadherin). Transcriptomic analysis showed tight paired clustering of UF-EOs with matched T-EOs across three independent patients. Both organoid types demonstrated equivalent hormone responsiveness, with progesterone-induced secretory differentiation evidenced by glandular folding, subnuclear vacuolization, glycogen accumulation, and upregulation of SPP1, PAEP, and 17HSD\u03b22. IUA-derived UF-EOs displayed 190 differentially expressed genes, with enrichment of cell cycle, TGF-\u03b2, and Hippo signaling pathways. TGF-\u03b22 and Smad2 were significantly upregulated and SOX9, PCNA, and Ki67 were downregulated, consistent with compromised regenerative capacity. HTR8\/SVneo spheroids were successfully microinjected into organoid lumens, with luminal localization observed at 24\u00a0h.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We have introduced uterine lavage fluid as a feasible source for generating endometrial organoids with equivalent fidelity to tissue-derived counterparts. UF-EOs provide a non-invasive alternative that enables organoid-based research in populations previously excluded from invasive sampling, including patients with intrauterine adhesions. Our findings demonstrate applications in disease mechanism investigation, endometrial receptivity assessment, and modeling of early embryo-epithelium interactions. Future studies employing larger cohorts and integrated multicellular systems will be essential to validate the clinical utility of this approach.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-026-05166-3","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:33:04Z","timestamp":1784043184000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A non-invasive, patient-derived organoid platform from uterine lavage fluid for modeling endometrial implantation and disease"],"prefix":"10.1186","volume":"17","author":[{"given":"Huiyu","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianli","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinshuang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hankun","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiying","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4193-7321","authenticated-orcid":false,"given":"Yanping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"5166_CR1","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1038\/nm.3012","volume":"18","author":"J Cha","year":"2012","unstructured":"Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18:1754\u201367. https:\/\/doi.org\/10.1038\/nm.3012.","journal-title":"Nat Med"},{"key":"5166_CR2","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1007\/s43032-021-00501-w","volume":"28","author":"Y Wei","year":"2021","unstructured":"Wei Y, Zhang C, Fan G, Meng L. Organoids as Novel Models for Embryo Implantation Study. Reprod Sci Thousand Oaks Calif. 2021;28:1637\u201343. https:\/\/doi.org\/10.1007\/s43032-021-00501-w.","journal-title":"Reprod Sci Thousand Oaks Calif"},{"key":"5166_CR3","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1242\/dev.148478","volume":"144","author":"M Boretto","year":"2017","unstructured":"Boretto M, Cox B, Noben M, Hendriks N, Fassbender A, Roose H, et al. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Dev Camb Engl. 2017;144:1775\u201386. https:\/\/doi.org\/10.1242\/dev.148478.","journal-title":"Dev Camb Engl"},{"key":"5166_CR4","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/ncb3516","volume":"19","author":"MY Turco","year":"2017","unstructured":"Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol. 2017;19:568\u201377. https:\/\/doi.org\/10.1038\/ncb3516.","journal-title":"Nat Cell Biol"},{"key":"5166_CR5","doi-asserted-by":"publisher","first-page":"23132","DOI":"10.1073\/pnas.1915389116","volume":"116","author":"HC Fitzgerald","year":"2019","unstructured":"Fitzgerald HC, Dhakal P, Behura SK, Schust DJ, Spencer TE. Self-renewing endometrial epithelial organoids of the human uterus. Proc Natl Acad Sci U S A. 2019;116:23132\u201342. https:\/\/doi.org\/10.1073\/pnas.1915389116.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"5166_CR6","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1093\/biolre\/ioaa124","volume":"103","author":"Z-Y Gu","year":"2020","unstructured":"Gu Z-Y, Jia S-Z, Liu S, Leng J-H. Endometrial Organoids: A New Model for the Research of Endometrial-Related Diseases\u2020. Biol Reprod. 2020;103:918\u201326. https:\/\/doi.org\/10.1093\/biolre\/ioaa124.","journal-title":"Biol Reprod"},{"key":"5166_CR7","doi-asserted-by":"publisher","first-page":"E1121","DOI":"10.3390\/cells9051121","volume":"9","author":"A Luddi","year":"2020","unstructured":"Luddi A, Pavone V, Semplici B, Governini L, Criscuoli M, Paccagnini E, et al. Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site. Cells. 2020;9:E1121. https:\/\/doi.org\/10.3390\/cells9051121.","journal-title":"Cells"},{"key":"5166_CR8","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/s42003-021-02194-y","volume":"4","author":"T Cindrova-Davies","year":"2021","unstructured":"Cindrova-Davies T, Zhao X, Elder K, Jones CJP, Moffett A, Burton GJ, et al. Menstrual flow as a non-invasive source of endometrial organoids. Commun Biol. 2021;4:651. https:\/\/doi.org\/10.1038\/s42003-021-02194-y.","journal-title":"Commun Biol"},{"key":"5166_CR9","doi-asserted-by":"publisher","first-page":"1220622","DOI":"10.3389\/fendo.2023.1220622","volume":"14","author":"SC Hewitt","year":"2023","unstructured":"Hewitt SC, Dickson MJ, Edwards N, Hampton K, Garantziotis S, DeMayo FJ. From cup to dish: how to make and use endometrial organoid and stromal cultures derived from menstrual fluid. Front Endocrinol. 2023;14:1220622. https:\/\/doi.org\/10.3389\/fendo.2023.1220622.","journal-title":"Front Endocrinol"},{"key":"5166_CR10","doi-asserted-by":"publisher","first-page":"hoaf063","DOI":"10.1093\/hropen\/hoaf063","volume":"2025","author":"FP Luongo","year":"2025","unstructured":"Luongo FP, Ortega Ba\u00f1o I, Belmonte G, Gentile M, Paccagnini E, Salumets A, et al. Modeling the window of implantation: insights from endometrial biopsy and menstrual blood-derived organoids and endometrial stromal cells. Hum Reprod Open. 2025;2025:hoaf063. https:\/\/doi.org\/10.1093\/hropen\/hoaf063.","journal-title":"Hum Reprod Open"},{"key":"5166_CR11","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1080\/00325481.1992.11701429","volume":"92","author":"PC Galle","year":"1992","unstructured":"Galle PC, McRae MA. Amenorrhea and chronic anovulation. Finding and addressing the underlying cause. Postgrad Med. 1992;92:255\u201360. https:\/\/doi.org\/10.1080\/00325481.1992.11701429.","journal-title":"Postgrad Med"},{"key":"5166_CR12","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1007\/s12020-023-03619-w","volume":"84","author":"B M\u0119czekalski","year":"2024","unstructured":"M\u0119czekalski B, Niwczyk O, Battipaglia C, Troia L, Kostrzak A, Bala G, et al. Neuroendocrine disturbances in women with functional hypothalamic amenorrhea: an update and future directions. Endocrine. 2024;84:769\u201385. https:\/\/doi.org\/10.1007\/s12020-023-03619-w.","journal-title":"Endocrine"},{"key":"5166_CR13","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S0140-6736(97)06297-1","volume":"350","author":"DT Baird","year":"1997","unstructured":"Baird DT, Amenorrhoea. Lancet Lond Engl. 1997;350:275\u20139. https:\/\/doi.org\/10.1016\/S0140-6736(97)06297-1.","journal-title":"Lancet Lond Engl"},{"key":"5166_CR14","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/S0140-6736(08)60346-3","volume":"371","author":"HD Nelson","year":"2008","unstructured":"Nelson HD, Menopause. Lancet Lond Engl. 2008;371:760\u201370. https:\/\/doi.org\/10.1016\/S0140-6736(08)60346-3.","journal-title":"Lancet Lond Engl"},{"key":"5166_CR15","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/s41587-019-0048-8","volume":"37","author":"F Schutgens","year":"2019","unstructured":"Schutgens F, Rookmaaker MB, Margaritis T, Rios A, Ammerlaan C, Jansen J, et al. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat Biotechnol. 2019;37:303\u201313. https:\/\/doi.org\/10.1038\/s41587-019-0048-8.","journal-title":"Nat Biotechnol"},{"key":"5166_CR16","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.fertnstert.2013.04.047","volume":"100","author":"C Chan","year":"2013","unstructured":"Chan C, Virtanen C, Winegarden NA, Colgan TJ, Brown TJ, Greenblatt EM. Discovery of biomarkers of endometrial receptivity through a minimally invasive approach: a validation study with implications for assisted reproduction. Fertil Steril. 2013;100:810\u20137. https:\/\/doi.org\/10.1016\/j.fertnstert.2013.04.047.","journal-title":"Fertil Steril"},{"key":"5166_CR17","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.fertnstert.2020.10.046","volume":"115","author":"T Li","year":"2021","unstructured":"Li T, Greenblatt EM, Shin ME, Brown TJ, Chan C. Cargo small non-coding RNAs of extracellular vesicles isolated from uterine fluid associate with endometrial receptivity and implantation success. Fertil Steril. 2021;115:1327\u201336. https:\/\/doi.org\/10.1016\/j.fertnstert.2020.10.046.","journal-title":"Fertil Steril"},{"key":"5166_CR18","doi-asserted-by":"publisher","unstructured":"Rodr\u00edguez-Eguren A, Bueno-Fernandez C, G\u00f3mez-\u00c1lvarez M, Franc\u00e9s-Herrero E, Pellicer A, Bellver J, et al. Evolution of biotechnological advances and regenerative therapies for endometrial disorders: a systematic review. Hum Reprod Update. 2024;dmae013. https:\/\/doi.org\/10.1093\/humupd\/dmae013.","DOI":"10.1093\/humupd\/dmae013"},{"key":"5166_CR19","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00281-024-01030-9","volume":"47","author":"G Zhao","year":"2024","unstructured":"Zhao G, Hu Y. Mechanistic insights into intrauterine adhesions. Semin Immunopathol. 2024;47:3. https:\/\/doi.org\/10.1007\/s00281-024-01030-9.","journal-title":"Semin Immunopathol"},{"key":"5166_CR20","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.freeradbiomed.2023.06.001","volume":"205","author":"Q Zhu","year":"2023","unstructured":"Zhu Q, Yao S, Ye Z, Jiang P, Wang H, Zhang X, et al. Ferroptosis contributes to endometrial fibrosis in intrauterine adhesions. Free Radic Biol Med. 2023;205:151\u201362. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2023.06.001.","journal-title":"Free Radic Biol Med"},{"key":"5166_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejogrb.2019.10.018","volume":"244","author":"Z Fei","year":"2020","unstructured":"Fei Z, Xin X, Fei H, Yuechong C. Meta-analysis of the use of hyaluronic acid gel to prevent intrauterine adhesions after miscarriage. Eur J Obstet Gynecol Reprod Biol. 2020;244:1\u20134. https:\/\/doi.org\/10.1016\/j.ejogrb.2019.10.018.","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"5166_CR22","doi-asserted-by":"publisher","first-page":"eadi4819","DOI":"10.1126\/sciadv.adi4819","volume":"10","author":"S Shibata","year":"2024","unstructured":"Shibata S, Endo S, Nagai LAE, Kobayashi H, Oike E, Kobayashi A. Modeling embryo-endometrial interface recapitulating human embryo implantation. Sci Adv. 2024;10:eadi4819. https:\/\/doi.org\/10.1126\/sciadv.adi4819.","journal-title":"Sci Adv"},{"key":"5166_CR23","doi-asserted-by":"publisher","first-page":"e376","DOI":"10.1016\/S2468-2667(19)30111-2","volume":"4","author":"AM van Eijk","year":"2019","unstructured":"van Eijk AM, Zulaika G, Lenchner M, Mason L, Sivakami M, Nyothach E, et al. Menstrual cup use, leakage, acceptability, safety, and availability: a systematic review and meta-analysis. Lancet Public Health. 2019;4:e376\u201393. https:\/\/doi.org\/10.1016\/S2468-2667(19)30111-2.","journal-title":"Lancet Public Health"},{"key":"5166_CR24","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/s41574-022-00725-z","volume":"18","author":"AR Murphy","year":"2022","unstructured":"Murphy AR, Campo H, Kim JJ. Strategies for modelling endometrial diseases. Nat Rev Endocrinol. 2022;18:727\u201343. https:\/\/doi.org\/10.1038\/s41574-022-00725-z.","journal-title":"Nat Rev Endocrinol"},{"key":"5166_CR25","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1186\/1477-7827-4-S1-S9","volume":"4","author":"BA Lessey","year":"2006","unstructured":"Lessey BA, Palomino WA, Apparao K, Young SL, Lininger RA. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol. 2006;4:S9. https:\/\/doi.org\/10.1186\/1477-7827-4-S1-S9.","journal-title":"Reprod Biol Endocrinol"},{"key":"5166_CR26","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1210\/jcem-67-2-334","volume":"67","author":"BA Lessey","year":"1988","unstructured":"Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab. 1988;67:334\u201340. https:\/\/doi.org\/10.1210\/jcem-67-2-334.","journal-title":"J Clin Endocrinol Metab"},{"key":"5166_CR27","doi-asserted-by":"publisher","first-page":"gaaa082","DOI":"10.1093\/molehr\/gaaa082","volume":"27","author":"S Marla","year":"2021","unstructured":"Marla S, Mortlock S, Houshdaran S, Fung J, McKinnon B, Holdsworth-Carson SJ, et al. Genetic risk factors for endometriosis near estrogen receptor 1 and coexpression of genes in this region in endometrium. Mol Hum Reprod. 2021;27:gaaa082. https:\/\/doi.org\/10.1093\/molehr\/gaaa082.","journal-title":"Mol Hum Reprod"},{"key":"5166_CR28","doi-asserted-by":"publisher","first-page":"e69603","DOI":"10.7554\/eLife.69603","volume":"10","author":"TM Rawlings","year":"2021","unstructured":"Rawlings TM, Makwana K, Taylor DM, Mol\u00e8 MA, Fishwick KJ, Tryfonos M, et al. Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife. 2021;10:e69603. https:\/\/doi.org\/10.7554\/eLife.69603.","journal-title":"eLife"},{"key":"5166_CR29","doi-asserted-by":"publisher","first-page":"e230429","DOI":"10.1530\/REP-23-0429","volume":"167","author":"IM Saadeldin","year":"2024","unstructured":"Saadeldin IM, Han A, Bang S, Kang H, Kim H, Abady MM, et al. Generation of porcine endometrial organoids and their use as a model for enhancing embryonic attachment and elongation. Reprod Camb Engl. 2024;167:e230429. https:\/\/doi.org\/10.1530\/REP-23-0429.","journal-title":"Reprod Camb Engl"},{"key":"5166_CR30","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/j.fertnstert.2008.02.096","volume":"89","author":"D Yu","year":"2008","unstructured":"Yu D, Wong Y-M, Cheong Y, Xia E, Li T-C. Asherman syndrome\u2013one century later. Fertil Steril. 2008;89:759\u201379. https:\/\/doi.org\/10.1016\/j.fertnstert.2008.02.096.","journal-title":"Fertil Steril"},{"key":"5166_CR31","doi-asserted-by":"publisher","first-page":"5890","DOI":"10.1038\/s41467-023-41656-1","volume":"14","author":"X Santamaria","year":"2023","unstructured":"Santamaria X, Roson B, Perez-Moraga R, Venkatesan N, Pardo-Figuerez M, Gonzalez-Fernandez J, et al. Decoding the endometrial niche of Asherman\u2019s Syndrome at single-cell resolution. Nat Commun. 2023;14:5890. https:\/\/doi.org\/10.1038\/s41467-023-41656-1.","journal-title":"Nat Commun"},{"key":"5166_CR32","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1016\/j.biocel.2007.10.024","volume":"40","author":"SE Gill","year":"2008","unstructured":"Gill SE, Parks WC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol. 2008;40:1334\u201347. https:\/\/doi.org\/10.1016\/j.biocel.2007.10.024.","journal-title":"Int J Biochem Cell Biol"},{"key":"5166_CR33","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s10815-018-1130-8","volume":"35","author":"L Aghajanova","year":"2018","unstructured":"Aghajanova L, Houshdaran S, Balayan S, Manvelyan E, Irwin JC, Huddleston HG, et al. In vitro evidence that platelet-rich plasma stimulates cellular processes involved in endometrial regeneration. J Assist Reprod Genet. 2018;35:757\u201370. https:\/\/doi.org\/10.1007\/s10815-018-1130-8.","journal-title":"J Assist Reprod Genet"},{"key":"5166_CR34","doi-asserted-by":"publisher","first-page":"e0146159","DOI":"10.1371\/journal.pone.0146159","volume":"10","author":"X Xue","year":"2015","unstructured":"Xue X, Chen Q, Zhao G, Zhao J-Y, Duan Z, Zheng P-S. The Overexpression of TGF-\u03b2 and CCN2 in Intrauterine Adhesions Involves the NF-\u03baB Signaling Pathway. PLoS ONE. 2015;10:e0146159. https:\/\/doi.org\/10.1371\/journal.pone.0146159.","journal-title":"PLoS ONE"},{"key":"5166_CR35","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1080\/15548627.2022.2038994","volume":"18","author":"Z Zhou","year":"2022","unstructured":"Zhou Z, Wang H, Zhang X, Song M, Yao S, Jiang P, et al. Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions. Autophagy. 2022;18:2427\u201342. https:\/\/doi.org\/10.1080\/15548627.2022.2038994.","journal-title":"Autophagy"},{"key":"5166_CR36","doi-asserted-by":"publisher","first-page":"6196","DOI":"10.3390\/ijms25116196","volume":"25","author":"L Wu","year":"2024","unstructured":"Wu L, Zhan Y, Wang Y. Semaglutide May Ameliorate Fibrosis and Inhibit Epithelial-Mesenchymal Transition in Intrauterine Adhesion Models. Int J Mol Sci. 2024;25:6196. https:\/\/doi.org\/10.3390\/ijms25116196.","journal-title":"Int J Mol Sci"},{"key":"5166_CR37","doi-asserted-by":"publisher","first-page":"15107","DOI":"10.1038\/s41598-025-97433-1","volume":"15","author":"P Li","year":"2025","unstructured":"Li P, Jian Y, Liu X, Pan L, Tan Z, Shan N. Single-cell transcriptome profiling of the human endometrium of patients with intrauterine adhesions. Sci Rep. 2025;15:15107. https:\/\/doi.org\/10.1038\/s41598-025-97433-1.","journal-title":"Sci Rep"},{"key":"5166_CR38","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12943-022-01569-x","volume":"21","author":"D Peng","year":"2022","unstructured":"Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-\u03b2 signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022;21:104. https:\/\/doi.org\/10.1186\/s12943-022-01569-x.","journal-title":"Mol Cancer"},{"key":"5166_CR39","doi-asserted-by":"publisher","first-page":"964","DOI":"10.3390\/ph16070964","volume":"16","author":"Y Wang","year":"2023","unstructured":"Wang Y, Wang Y, Wu Y, Wang Y. Dulaglutide Ameliorates Intrauterine Adhesion by Suppressing Inflammation and Epithelial-Mesenchymal Transition via Inhibiting the TGF-\u03b2\/Smad2 Signaling Pathway. Pharm Basel Switz. 2023;16:964. https:\/\/doi.org\/10.3390\/ph16070964.","journal-title":"Pharm Basel Switz"},{"key":"5166_CR40","doi-asserted-by":"publisher","first-page":"2732","DOI":"10.4103\/0366-6999.218013","volume":"130","author":"H-Y Zhu","year":"2017","unstructured":"Zhu H-Y, Ge T-X, Pan Y-B, Zhang S-Y. Advanced Role of Hippo Signaling in Endometrial Fibrosis: Implications for Intrauterine Adhesion. Chin Med J (Engl). 2017;130:2732\u20137. https:\/\/doi.org\/10.4103\/0366-6999.218013.","journal-title":"Chin Med J (Engl)"},{"key":"5166_CR41","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s13287-019-1332-8","volume":"10","author":"Y Yao","year":"2019","unstructured":"Yao Y, Chen R, Wang G, Zhang Y, Liu F. Exosomes derived from mesenchymal stem cells reverse EMT via TGF-\u03b21\/Smad pathway and promote repair of damaged endometrium. Stem Cell Res Ther. 2019;10:225. https:\/\/doi.org\/10.1186\/s13287-019-1332-8.","journal-title":"Stem Cell Res Ther"},{"key":"5166_CR42","doi-asserted-by":"publisher","first-page":"3509","DOI":"10.1021\/acsnano.3c10884","volume":"18","author":"H Liu","year":"2024","unstructured":"Liu H, Zhang X, Zhang M, Zhang S, Li J, Zhang Y, et al. Mesenchymal Stem Cell Derived Exosomes Repair Uterine Injury by Targeting Transforming Growth Factor-\u03b2 Signaling. ACS Nano. 2024;18:3509\u201319. https:\/\/doi.org\/10.1021\/acsnano.3c10884.","journal-title":"ACS Nano"},{"key":"5166_CR43","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13287-025-04183-y","volume":"16","author":"J Song","year":"2025","unstructured":"Song J, Li M, Tao Y, Li Y, Mai C, Zhang J, et al. Enhanced myofibroblast differentiation of eMSCs in intrauterine adhesions. Stem Cell Res Ther. 2025;16:35. https:\/\/doi.org\/10.1186\/s13287-025-04183-y.","journal-title":"Stem Cell Res Ther"},{"key":"5166_CR44","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1093\/stcltm\/szad007","volume":"12","author":"Y Lin","year":"2023","unstructured":"Lin Y, Li Y, Chen P, Zhang Y, Sun J, Sun X, et al. Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers. Stem Cells Transl Med. 2023;12:154\u201368. https:\/\/doi.org\/10.1093\/stcltm\/szad007.","journal-title":"Stem Cells Transl Med"},{"key":"5166_CR45","doi-asserted-by":"publisher","first-page":"110673","DOI":"10.1016\/j.ygeno.2023.110673","volume":"115","author":"L Gao","year":"2023","unstructured":"Gao L, Liang E, Zhang D, Zhang Y, Zhang X, Jiang G, et al. Epigenetic alternations and targeted therapy in intrauterine adhesion: A comparative study. Genomics. 2023;115:110673. https:\/\/doi.org\/10.1016\/j.ygeno.2023.110673.","journal-title":"Genomics"},{"key":"5166_CR46","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1093\/humrep\/dey336","volume":"34","author":"DK Hapangama","year":"2019","unstructured":"Hapangama DK, Drury J, Da Silva L, Al-Lamee H, Earp A, Valentijn AJ, et al. Abnormally located SSEA1+\/SOX9\u2009+\u2009endometrial epithelial cells with a basalis-like phenotype in the eutopic functionalis layer may play a role in the pathogenesis of endometriosis. Hum Reprod. 2019;34:56\u201368. https:\/\/doi.org\/10.1093\/humrep\/dey336.","journal-title":"Hum Reprod"},{"key":"5166_CR47","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/ng.722","volume":"43","author":"K Furuyama","year":"2011","unstructured":"Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43:34\u201341. https:\/\/doi.org\/10.1038\/ng.722.","journal-title":"Nat Genet"},{"key":"5166_CR48","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/375159a0","volume":"375","author":"Y Luo","year":"1995","unstructured":"Luo Y, Hurwitz J, Massagu\u00e9 J. Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1. Nature. 1995;375:159\u201361. https:\/\/doi.org\/10.1038\/375159a0.","journal-title":"Nature"},{"key":"5166_CR49","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1093\/aob\/mcq243","volume":"107","author":"W Strzalka","year":"2011","unstructured":"Strzalka W, Ziemienowicz A. Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. Ann Bot. 2011;107:1127\u201340. https:\/\/doi.org\/10.1093\/aob\/mcq243.","journal-title":"Ann Bot"},{"key":"5166_CR50","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1007\/s10815-024-03173-y","volume":"41","author":"BN Bui","year":"2024","unstructured":"Bui BN, Ardisasmita AI, van de Vliert FH, Abendroth MS, van Hoesel M, Mackens S, et al. Enrichment of cell cycle pathways in progesterone-treated endometrial organoids of infertile women compared to fertile women. J Assist Reprod Genet. 2024;41:2405\u201318. https:\/\/doi.org\/10.1007\/s10815-024-03173-y.","journal-title":"J Assist Reprod Genet"},{"key":"5166_CR51","doi-asserted-by":"publisher","first-page":"3935","DOI":"10.1016\/j.bioactmat.2021.04.006","volume":"6","author":"X Jiang","year":"2021","unstructured":"Jiang X, Li X, Fei X, Shen J, Chen J, Guo M, et al. Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome. Bioact Mater. 2021;6:3935\u201346. https:\/\/doi.org\/10.1016\/j.bioactmat.2021.04.006.","journal-title":"Bioact Mater"},{"key":"5166_CR52","doi-asserted-by":"publisher","first-page":"2627","DOI":"10.7150\/ijbs.69410","volume":"18","author":"H Zhang","year":"2022","unstructured":"Zhang H, Xu D, Li Y, Lan J, Zhu Y, Cao J, et al. Organoid Transplantation Can Improve Reproductive Prognosis by Promoting Endometrial Repair in Mice. Int J Biol Sci. 2022;18:2627\u201338. https:\/\/doi.org\/10.7150\/ijbs.69410.","journal-title":"Int J Biol Sci"},{"key":"5166_CR53","doi-asserted-by":"publisher","first-page":"954","DOI":"10.7150\/thno.90538","volume":"14","author":"S-Y Hwang","year":"2024","unstructured":"Hwang S-Y, Lee D, Lee G, Ahn J, Lee Y-G, Koo HS, et al. Endometrial organoids: a reservoir of functional mitochondria for uterine repair. Theranostics. 2024;14:954\u201372. https:\/\/doi.org\/10.7150\/thno.90538.","journal-title":"Theranostics"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-026-05166-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-026-05166-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-026-05166-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:24:53Z","timestamp":1791512693000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13287-026-05166-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5166"],"URL":"https:\/\/doi.org\/10.1186\/s13287-026-05166-3","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]},"assertion":[{"value":"22 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (project title: \u201cStudy on the mechanism of ER key genes in endometrial receptivity abnormalities in recurrent implantation failure\u201d, approval number: 2022007, date of approval: October 10, 2022). Written informed consent was obtained from all participants for the collection and use of uterine lavage fluid and endometrial samples. All procedures were performed in accordance with the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"361"}}