{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:13:14Z","timestamp":1787026394434,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1S00823N"],"award-info":[{"award-number":["1S00823N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    The uterus-lining endometrium is essential to mammalian reproduction, receiving and accommodating the embryo for proper development. Despite its key role, mechanisms underlying endometrial biology (menstrual cycling, embryo interaction) and disease are not well understood. Its hidden location in the womb, and thereby-associated lack of suitable research models, contribute to this knowledge gap. Recently, 3D organoid models have been developed from both healthy and diseased endometrium. These organoids closely recapitulate the tissue\u2019s epithelium phenotype and (patho)biology, including\n                    <jats:italic>in vitro<\/jats:italic>\n                    reproduction of the menstrual cycle. Typically, organoids are grown in a scaffold made of surrogate tissue extracellular matrix (ECM), with mouse tumor basement membrane extracts being the most commonly used. However, important limitations apply including their lack of standardization and xeno-derivation which strongly hinder clinical translation. Therefore, researchers are actively seeking better alternatives including fully defined matrices for faithful and efficient growth of organoids. Here, we summarize the state-of-the-art regarding matrix scaffolds to grow endometrium-derived organoids as well as more advanced organoid-based 3D models. We discuss remaining shortcomings and challenges to advance endometrial organoids toward defined and standardized tools for applications in basic research and translational\/clinical fields.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2023.1240064","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T02:19:56Z","timestamp":1691720396000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Matrix scaffolds for endometrium-derived organoid models"],"prefix":"10.3389","volume":"14","author":[{"given":"Silke","family":"De Vriendt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia Mesias","family":"Casares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Vankelecom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/S41574-022-00725-Z","article-title":"Strategies for modelling endometrial diseases","volume":"18","author":"Murphy","year":"2022","journal-title":"Nat Rev Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/jpm12071048","article-title":"Modeling endometrium biology and disease","volume":"12","author":"Maenhoudt","year":"2022","journal-title":"J Pers Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/humupd\/dmac025","article-title":"Bioengineering trends in female reproduction: a systematic review","volume":"28","author":"Franc\u00e9s-Herrero","year":"2022","journal-title":"Front Bioeng Biotechnol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1242\/dev.148478","article-title":"Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability","volume":"144","author":"Boretto","year":"2017","journal-title":"Development"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3516","article-title":"Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium","volume":"19","author":"Turco","year":"2017","journal-title":"Nat Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0360-z","article-title":"Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening","volume":"21","author":"Boretto","year":"2019","journal-title":"Nat Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-021-00471-z","article-title":"Endometrial organoids: a rising star for research on endometrial development and associated diseases","volume":"28","author":"Song","year":"2021","journal-title":"Reprod Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.844623","article-title":"Human endometrial organoids: recent research progress and potential applications","volume":"10","author":"Lou","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012419-032611","article-title":"Human organoids: tools for understanding biology and treating diseases","volume":"15","author":"Schutgens","year":"2020","journal-title":"Annu Rev Pathol Mech Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2005.05.004","article-title":"Matrigel: basement membrane matrix with biological activity","volume":"15","author":"Kleinman","year":"2005","journal-title":"Semin Cancer Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2208040119","article-title":"Bovine and human endometrium-derived hydrogels support organoid culture from healthy and cancerous tissues","volume":"119","author":"Jamaluddin","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/jpm11060504","article-title":"Improved models of human endometrial organoids based on hydrogels from decellularized endometrium","volume":"11","author":"Franc\u00e9s-Herrero","year":"2021","journal-title":"J Pers Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118054119","article-title":"Development and characterization of human fetal female reproductive tract organoids to understand M\u00fcllerian duct anoMalies","volume":"119","author":"Venkata","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.69603","article-title":"Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids","volume":"10","author":"Rawlings","year":"2021","journal-title":"Elife"},{"key":"B15","doi-asserted-by":"publisher","first-page":"20190079","DOI":"10.1098\/rsfs.2019.0079","article-title":"Generation of a three-dimensional collagen scaffold-based model of the human endometrium","volume":"10","author":"Abbas","year":"2020","journal-title":"Interface Focus"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/2021.09.30.462577","article-title":"Organoid coculture model of the cycling human endometrium in a fully-defined synthetic extracellular matrix reveals epithelial-stromal crosstalk","author":"Gnecco","year":"2022"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120125","article-title":"Fully synthetic matrices for in vitro culture of primary human intestinal enteroids and endometrial organoids","volume":"254","author":"Hernandez-Gordillo","year":"2020","journal-title":"Biomaterials"},{"key":"B18","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2612-2","article-title":"Effects of extracellular matrix viscoelasticity on cellular behaviour","volume":"584","author":"Chaudhuri","year":"2020","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/iox039","article-title":"Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment","volume":"96","author":"Olalekan","year":"2017","journal-title":"Biol Reprod"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1530\/JRF.0.1080147","article-title":"Alterations in distribution and composition of the extracellular matrix during decidualization of the human endometrium","volume":"108","author":"Iwahashi","year":"1996","journal-title":"J Reprod Fertil"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199901)187:2<242::AID-PATH221>3.0.CO;2-T","article-title":"Tenascin is differentially expressed in endometrium and endometriosis","volume":"187","author":"Harrington","year":"1999","journal-title":"J Pathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1177\/1535370220938741","article-title":"The role of extracellular matrix in normal and pathological pregnancy: future applications of microphysiological systems in reproductive medicine","volume":"245","author":"O\u2019Connor","year":"2020","journal-title":"Exp Biol Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1093\/humrep\/dez139","article-title":"Tissue stiffness at the human maternal\u2013fetal interface","volume":"34","author":"Abbas","year":"2019","journal-title":"Hum Reprod"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00583-1","article-title":"Cell\u2013extracellular matrix mechanotransduction in 3D","volume":"24","author":"Saraswathibhatla","year":"2023","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222787110","article-title":"Strain history dependence of the nonlinear stress response of fibrin and collagen networks","volume":"110","author":"M\u00fcnster","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/path.1400","article-title":"Extracellular matrix remodelling: the role of matrix metalloproteinases","volume":"200","author":"Stamenkovic","year":"2003","journal-title":"J Pathol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065463","article-title":"Changes in the extracellular matrix in endometrial and cervical cancer: a systematic review","volume":"24","author":"Pade\u017enik","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0134-2","article-title":"Integrins as biomechanical sensors of the microenvironment","volume":"20","author":"Kechagia","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.8714","article-title":"Overexpression of the matrix metalloproteinase 11 gene is a potential biomarker for type 1 endometrial cancer","volume":"16","author":"G\u00f3mez-Mac\u00edas","year":"2018","journal-title":"Oncol Lett"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS21082840","article-title":"Expression of matrix metalloproteinases and their inhibitors in endometrium: high levels in endometriotic lesions","volume":"21","author":"Luddi","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.200900758","article-title":"Matrigel: a complex protein mixture required for optimal growth of cell culture","volume":"10","author":"Hughes","year":"2010","journal-title":"Proteomics"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1530\/REP-20-0266","article-title":"Hormone-responsive organoids from domestic mare and endangered Przewalski\u2019s horse endometrium","volume":"160","author":"Thompson","year":"2020","journal-title":"Reproduction"},{"key":"B34","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/s42003-021-02194-y","article-title":"Menstrual flow as a non-invasive source of endometrial organoids","volume":"4","author":"Cindrova-Davies","year":"2021","journal-title":"Commun Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051121","article-title":"Organoids of human endometrium: a powerful in vitro model for the endometrium-embryo cross-talk at the implantation site","volume":"9","author":"Luddi","year":"2020","journal-title":"Cells"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-022-00961-5","article-title":"Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues","volume":"24","author":"Tan","year":"2022","journal-title":"Nat Cell Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"dmm049379","DOI":"10.1242\/dmm.049379","article-title":"Endometrial organoids derived from Mayer\u2013Rokitansky\u2013K\u00fcster\u2013Hauser syndrome patients provide insights into disease-causing pathways","volume":"15","author":"Brucker","year":"2022","journal-title":"Dis Model Mech"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00972-2","article-title":"Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro","volume":"53","author":"Garcia-Alonso","year":"2021","journal-title":"Nat Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00416","article-title":"Murine endometrial organoids to model Chlamydia infection","volume":"10","author":"Bishop","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04267-8","article-title":"Human blastoids model blastocyst development and implantation","volume":"601","author":"Kagawa","year":"2022","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.repbio.2021.100564","article-title":"Bio-modulated mice epithelial endometrial organoids by low-level laser therapy serves as an in vitro model for endometrial regeneration","volume":"21","author":"Gebril","year":"2021","journal-title":"Reprod Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.69410","article-title":"Organoid transplantation can improve reproductive prognosis by promoting endometrial repair in mice","volume":"18","author":"Zhang","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-020-0199-8","article-title":"Synthetic alternatives to matrigel","volume":"5","author":"Aisenbrey","year":"2020","journal-title":"Nat Rev Mater"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2021.639688","article-title":"A natural xenogeneic endometrial extracellular matrix hydrogel toward improving current human in vitro models and future in vivo applications","volume":"9","author":"L\u00f3pez-Mart\u00ednez","year":"2021","journal-title":"Front Bioeng Biotechnol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.placenta.2014.10.012","article-title":"Collagen type IV at the fetal\u2013maternal interface","volume":"36","author":"Oefner","year":"2015","journal-title":"Placenta"},{"key":"B46","unstructured":"BagleyB\n          Advanced biomatrix. Collagen gelation kinetics and shear modulus2019"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1089\/ten.teb.2014.0086","article-title":"Review of collagen I hydrogels for bioengineered tissue microenvironments: characterization of mechanics, structure, and transport","volume":"20","author":"Antoine","year":"2014","journal-title":"Tissue Eng Part B Rev"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.actbio.2016.11.068","article-title":"Extracellular matrix hydrogels from decellularized tissues: structure and function","volume":"49","author":"Saldin","year":"2017","journal-title":"Acta Biomater"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201801621","article-title":"Growth of epithelial organoids in a defined hydrogel","volume":"30","author":"Broguiere","year":"2018","journal-title":"Adv Mater"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41563-022-01400-4","article-title":"Matrix viscoelasticity controls spatio-temporal tissue organization","volume":"22","author":"Elosegui-Artola","year":"2023","journal-title":"Nat Mater"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00414","article-title":"Alginate formulations: current developments in the race for hydrogel-based cardiac regeneration","volume":"8","author":"Cattelan","year":"2020","journal-title":"Front Bioeng Biotechnol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nature20168","article-title":"Designer matrices for intestinal stem cell and organoid culture","volume":"539","author":"Gjorevski","year":"2016","journal-title":"Nature"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41563-021-01085-1","article-title":"A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids","volume":"21","author":"Below","year":"2022","journal-title":"Nat Mater"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c00046","article-title":"Mechanics of 3D cell\u2013hydrogel interactions: experiments, models, and mechanisms","volume":"121","author":"Vernerey","year":"2021","journal-title":"Chem Rev"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201705564","article-title":"Near-infrared light-sensitive polyvinyl alcohol hydrogel photoresist for spatiotemporal control of cell-instructive 3D microenvironments","volume":"30","author":"Qin","year":"2018","journal-title":"Adv Mater"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.104971","article-title":"A scalable and tunable thermoreversible polymer for 3D human pluripotent stem cell biOmanufacturing","volume":"25","author":"Johnson","year":"2022","journal-title":"iScience"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202001797","article-title":"Polyisocyanide hydrogels as a tunable platform for mammary gland organoid formation","volume":"7","author":"Zhang","year":"2020","journal-title":"Adv Sci"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2019","article-title":"Physiology of the endometrium and regulation of menstruation","volume":"100","author":"Critchley","year":"2020","journal-title":"Physiol Rev"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3390\/cimb44090260","article-title":"Inflammation-related molecules at the maternal-fetal interface during pregnancy and in pathologically altered endometrium","volume":"44","author":"Sieg","year":"2022","journal-title":"Curr Issues Mol Biol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"jcs252403","DOI":"10.1242\/jcs.252403","article-title":"An endometrial organoid model of interactions between Chlamydia and epithelial and immune cells","volume":"134","author":"Dolat","year":"2021","journal-title":"J Cell Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1240064\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T02:19:59Z","timestamp":1691720399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1240064\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":60,"alternative-id":["10.3389\/fendo.2023.1240064"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1240064","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]},"article-number":"1240064"}}