{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:11:32Z","timestamp":1778735492785,"version":"3.51.4"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S009930\/1"],"award-info":[{"award-number":["MR\/S009930\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R017336\/1"],"award-info":[{"award-number":["MR\/R017336\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000672","name":"Pathological Society of Great Britain and Ireland","doi-asserted-by":"publisher","award":["TSGS 1019"],"award-info":[{"award-number":["TSGS 1019"]}],"id":[{"id":"10.13039\/501100000672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000672","name":"Pathological Society of Great Britain and Ireland","doi-asserted-by":"publisher","award":["CLSG 1021"],"award-info":[{"award-number":["CLSG 1021"]}],"id":[{"id":"10.13039\/501100000672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000672","name":"Pathological Society of Great Britain and Ireland","doi-asserted-by":"publisher","award":["CLSG 1021"],"award-info":[{"award-number":["CLSG 1021"]}],"id":[{"id":"10.13039\/501100000672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC Impact Accelerator Account"},{"DOI":"10.13039\/501100020410","name":"John and Lucille Van Geest Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018063","name":"Bowel Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000849","name":"National Centre for the Replacement, Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/X002101\/1"],"award-info":[{"award-number":["NC\/X002101\/1"]}],"id":[{"id":"10.13039\/501100000849","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The intestinal mucosa is a complex functional layer which is formed from a diverse range of cell types that include epithelial cells (within crypts and villi) and an array of mesenchymal cells. Many intestinal diseases involve loss of the surface mucosa which can be difficult to restore, and which delays healing and return to normal function. We reason that development of a transplantable intestinal mucosal tissue graft may be a potential therapeutic strategy to aid healing. To be clinically useful, such a tissue graft would need to be capable of rapid production, avoid the risk of host rejection and be demonstrably safe. To create a potential intestinal graft, we developed a novel early-stage human induced pluripotent stem cell (hiPSC) co-differentiation platform capable of generating multiple intestinal cell lineages (epithelial, mesenchymal and endothelial) in 8 days. This protocol is simple to implement, serum-free and greatly reduces the use of animal products. We confirmed the identity of cells by demonstrating that these cells had RNA and protein expression profiles typical of intestinal cell lineages. In particular, we used bulk and single-cell RNA sequencing to characterise global cellular transcriptional profiles robustly and showed that the cells have intestinal identity with early polarisation towards colonic differentiation. The results were replicated across multiple hiPSC lines and in an independent centre. We further cultured the derived cells on collagen hydrogels to form colon-like intestinal patches (CL-IPs). When transplanted into mouse subcutis, CL-IPs formed into colon-like tissue structures, including crypts, stromal and muscle layers. They also developed human-origin vasculature which underwent anastomosis with the murine vasculature to transport murine blood into the graft. Teratoma assays and molecular analyses showed no evidence of residual pluripotency. While at an early stage, this platform shows great potential for further development as a potential source for novel intestinal mucosal regeneration therapy. In addition, the platform is physiologically relevant and thus shows promise as the basis for a new generation of in vitro models of intestinal pathobiology.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1186\/s13287-026-05006-4","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T08:07:30Z","timestamp":1775722050000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generation of biologically responsive colon-like intestinal tissue patches from human induced pluripotent stem cells using a rapid co-differentiation platform"],"prefix":"10.1186","volume":"17","author":[{"given":"William","family":"Dalleywater","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander V.","family":"Predeus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Batuhan","family":"Cakir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Mazin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayakumar","family":"Vadakekolathu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Rutella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian L.","family":"Meakin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison A.","family":"Ritchie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamir","family":"Montazid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara Cuevas","family":"Oca\u00f1a","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Wright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Sang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Santoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Bills","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Declan","family":"Sculthorpe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rasa","family":"Elmentaite","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Teichmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shazia","family":"Irshad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Silver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricky D.","family":"Wildman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas R. F.","family":"Hannan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felicity R. A. J.","family":"Rose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Ilyas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"issue":"3","key":"5006_CR1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1136\/flgastro-2014-100514","volume":"6","author":"G Nivedita","year":"2015","unstructured":"Nivedita G, Purushothaman P. A UK cost of care model for inflammatory bowel disease. Frontline Gastroenterol. 2015;6(3):169.","journal-title":"Frontline Gastroenterol"},{"issue":"6","key":"5006_CR2","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.devcel.2020.11.010","volume":"55","author":"R Elmentaite","year":"2020","unstructured":"Elmentaite R, Ross ADB, Roberts K, James KR, Ortmann D, Gomes T, et al. Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn\u2019s Disease. Dev Cell. 2020;55(6):771\u2013e835.","journal-title":"Dev Cell"},{"issue":"9","key":"5006_CR3","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1093\/ibd\/izad044","volume":"29","author":"D Rutherford","year":"2023","unstructured":"Rutherford D, Ho G-T. Therapeutic Potential of Human Intestinal Organoids in Tissue Repair Approaches in Inflammatory Bowel Diseases. Inflamm Bowel Dis. 2023;29(9):1488\u201398.","journal-title":"Inflamm Bowel Dis"},{"issue":"5","key":"5006_CR4","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.3390\/jcm9051273","volume":"9","author":"K Yeshi","year":"2020","unstructured":"Yeshi K, Ruscher R, Hunter L, Daly NL, Loukas A, Wangchuk P. Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products. J Clin Med. 2020;9(5):1273.","journal-title":"J Clin Med"},{"issue":"3","key":"5006_CR5","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1038\/s41596-021-00658-3","volume":"17","author":"S Watanabe","year":"2022","unstructured":"Watanabe S, Kobayashi S, Ogasawara N, Okamoto R, Nakamura T, Watanabe M, et al. Transplantation of intestinal organoids into a mouse model of colitis. Nat Protoc. 2022;17(3):649\u201371.","journal-title":"Nat Protoc"},{"issue":"7875","key":"5006_CR6","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/s41586-021-03852-1","volume":"597","author":"R Elmentaite","year":"2021","unstructured":"Elmentaite R, Kumasaka N, Roberts K, Fleming A, Dann E, King HW, et al. Cells of the human intestinal tract mapped across space and time. Nature. 2021;597(7875):250\u20135.","journal-title":"Nature"},{"issue":"2","key":"5006_CR7","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.cell.2018.08.067","volume":"175","author":"J Kinchen","year":"2018","unstructured":"Kinchen J, Chen HH, Parikh K, Antanaviciute A, Jagielowicz M, Fawkner-Corbett D, et al. Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease. Cell. 2018;175(2):372\u2013. \u2013\u200986.e17.","journal-title":"Cell"},{"issue":"3","key":"5006_CR8","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/S0168-9525(99)01957-5","volume":"16","author":"A Grapin-Botton","year":"2000","unstructured":"Grapin-Botton A, Melton DA. Endoderm development: from patterning to organogenesis. Trends Genet. 2000;16(3):124\u201330.","journal-title":"Trends Genet"},{"issue":"7","key":"5006_CR9","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1053\/j.gastro.2023.02.030","volume":"164","author":"S He","year":"2023","unstructured":"He S, Lei P, Kang W, Cheung P, Xu T, Mana M, et al. Stiffness Restricts the Stemness of the Intestinal Stem Cells and Skews Their Differentiation Toward Goblet Cells. Gastroenterology. 2023;164(7):1137\u2013e5115.","journal-title":"Gastroenterology"},{"issue":"1","key":"5006_CR10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrm3721","volume":"15","author":"N Barker","year":"2014","unstructured":"Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2014;15(1):19\u201333.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"5006_CR11","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s11626-020-00500-2","volume":"57","author":"PJ Hayden","year":"2021","unstructured":"Hayden PJ, Harbell JW. Special review series on 3D organotypic culture models: Introduction and historical perspective. Vitro Cell Dev Biology - Anim. 2021;57(2):95\u2013103.","journal-title":"Vitro Cell Dev Biology - Anim"},{"issue":"1","key":"5006_CR12","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/s41418-020-00665-z","volume":"28","author":"J Sprangers","year":"2021","unstructured":"Sprangers J, Zaalberg IC, Maurice MM. Organoid-based modeling of intestinal development, regeneration, and repair. Cell Death Differ. 2021;28(1):95\u2013107.","journal-title":"Cell Death Differ"},{"issue":"10","key":"5006_CR13","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1038\/s41591-020-1024-z","volume":"26","author":"L Meran","year":"2020","unstructured":"Meran L, Massie I, Campinoti S, Weston AE, Gaifulina R, Tullie L, et al. Engineering transplantable jejunal mucosal grafts using patient-derived organoids from children with intestinal failure. Nat Med. 2020;26(10):1593\u2013601.","journal-title":"Nat Med"},{"issue":"5560","key":"5006_CR14","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1126\/science.1069883","volume":"295","author":"EH Davidson","year":"2002","unstructured":"Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh C-H, et al. A Genomic Regulatory Network for Development. Science. 2002;295(5560):1669\u201378.","journal-title":"Science"},{"issue":"20","key":"5006_CR15","doi-asserted-by":"publisher","first-page":"3883","DOI":"10.1007\/s00018-015-1975-2","volume":"72","author":"L Le Guen","year":"2015","unstructured":"Le Guen L, Marchal S, Faure S, de Santa Barbara P. Mesenchymal\u2013epithelial interactions during digestive tract development and epithelial stem cell regeneration. Cell Mol Life Sci. 2015;72(20):3883\u201396.","journal-title":"Cell Mol Life Sci"},{"issue":"3","key":"5006_CR16","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.cell.2020.12.016","volume":"184","author":"D Fawkner-Corbett","year":"2021","unstructured":"Fawkner-Corbett D, Antanaviciute A, Parikh K, Jagielowicz M, Ger\u00f3s AS, Gupta T, et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell. 2021;184(3):810\u2013e2623.","journal-title":"Cell"},{"issue":"1","key":"5006_CR17","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.stem.2017.05.020","volume":"21","author":"JO M\u00fanera","year":"2017","unstructured":"M\u00fanera JO, Sundaram N, Rankin SA, Hill D, Watson C, Mahe M, et al. Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. Cell Stem Cell. 2017;21(1):51\u2013e646.","journal-title":"Cell Stem Cell"},{"issue":"7332","key":"5006_CR18","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature09691","volume":"470","author":"JR Spence","year":"2011","unstructured":"Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470(7332):105\u20139.","journal-title":"Nature"},{"issue":"4","key":"5006_CR19","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1242\/dev.097386","volume":"141","author":"JM Wells","year":"2014","unstructured":"Wells JM, Spence JR. How to make an intestine. Development. 2014;141(4):752\u201360.","journal-title":"Development"},{"issue":"8","key":"5006_CR20","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.molmed.2018.06.001","volume":"24","author":"MH Macedo","year":"2018","unstructured":"Macedo MH, Ara\u00fajo F, Mart\u00ednez E, Barrias C, Sarmento B. iPSC-Derived Enterocyte-like Cells for Drug Absorption and Metabolism Studies. Trends Mol Med. 2018;24(8):696\u2013708.","journal-title":"Trends Mol Med"},{"issue":"1","key":"5006_CR21","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/s41467-019-13916-6","volume":"11","author":"A Mithal","year":"2020","unstructured":"Mithal A, Capilla A, Heinze D, Berical A, Villacorta-Martin C, Vedaie M, et al. Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells. Nat Commun. 2020;11(1):215.","journal-title":"Nat Commun"},{"issue":"11","key":"5006_CR22","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1016\/j.stem.2023.10.002","volume":"30","author":"JO M\u00fanera","year":"2023","unstructured":"M\u00fanera JO, Kechele DO, Bouffi C, Qu N, Jing R, Maity P, et al. Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon. Cell Stem Cell. 2023;30(11):1434\u2013e519.","journal-title":"Cell Stem Cell"},{"issue":"7","key":"5006_CR23","doi-asserted-by":"publisher","first-page":"e0134551","DOI":"10.1371\/journal.pone.0134551","volume":"10","author":"K Tamminen","year":"2015","unstructured":"Tamminen K, Balboa D, Toivonen S, Pakarinen MP, Wiener Z, Alitalo K, et al. Intestinal Commitment and Maturation of Human Pluripotent Stem Cells Is Independent of Exogenous FGF4 and R-spondin1. PLoS ONE. 2015;10(7):e0134551.","journal-title":"PLoS ONE"},{"issue":"1","key":"5006_CR24","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1111\/j.1741-4520.2003.00004.x","volume":"44","author":"N Yahagi","year":"2004","unstructured":"Yahagi N, Kosaki R, Ito T, Mitsuhashi T, Shimada H, Tomita M, et al. Position-specific expression of Hox genes along the gastrointestinal tract. Congenit Anom. 2004;44(1):18\u201326.","journal-title":"Congenit Anom"},{"issue":"12","key":"5006_CR25","doi-asserted-by":"publisher","first-page":"3281","DOI":"10.1016\/j.cell.2021.04.028","volume":"184","author":"Q Yu","year":"2021","unstructured":"Yu Q, Kilik U, Holloway EM, Tsai Y-H, Harmel C, Wu A, et al. Charting human development using a multi-endodermal organ atlas and organoid models. Cell. 2021;184(12):3281\u2013e9822.","journal-title":"Cell"},{"issue":"26","key":"5006_CR26","first-page":"5876","volume":"186","author":"X Chuan","year":"2023","unstructured":"Chuan X, Martin P, Simone W, Laura J, Benjamin JS, Regina H, et al. Automatic cell type harmonization and integration across Human Cell Atlas datasets. bioRxiv. 2023;186(26):5876\u201391.","journal-title":"bioRxiv"},{"issue":"7710","key":"5006_CR27","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/s41586-018-0190-3","volume":"558","author":"B Degirmenci","year":"2018","unstructured":"Degirmenci B, Valenta T, Dimitrieva S, Hausmann G, Basler K. GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature. 2018;558(7710):449\u201353.","journal-title":"Nature"},{"key":"5006_CR28","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1007\/978-1-0716-3076-1_13","volume-title":"Intestinal Differentiated Cells: Methods and Protocols","author":"W Dalleywater","year":"2023","unstructured":"Dalleywater W, Wheat F, Sculthorpe D, Hyland G, Ilyas M. Vitro Culture and Histological Evaluation of 3D Organotypic Cultures. In: Ord\u00f3\u00f1ez-Mor\u00e1n P, editor. Intestinal Differentiated Cells: Methods and Protocols. New York, NY: Springer US; 2023. pp. 155\u201370."},{"issue":"1","key":"5006_CR29","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41575-018-0081-y","volume":"16","author":"H Gehart","year":"2019","unstructured":"Gehart H, Clevers H. Tales from the crypt: new insights into intestinal stem cells. Nat Reviews Gastroenterol Hepatol. 2019;16(1):19\u201334.","journal-title":"Nat Reviews Gastroenterol Hepatol"},{"issue":"3","key":"5006_CR30","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.stem.2020.01.008","volume":"26","author":"N McCarthy","year":"2020","unstructured":"McCarthy N, Manieri E, Storm EE, Saadatpour A, Luoma AM, Kapoor VN, et al. Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient. Cell Stem Cell. 2020;26(3):391\u2013e4025.","journal-title":"Cell Stem Cell"},{"issue":"12","key":"5006_CR31","doi-asserted-by":"publisher","first-page":"3072","DOI":"10.1016\/j.cell.2024.04.039","volume":"187","author":"TR Huycke","year":"2024","unstructured":"Huycke TR, H\u00e4kkinen TJ, Miyazaki H, Srivastava V, Barruet E, McGinnis CS, et al. Patterning and folding of intestinal villi by active mesenchymal dewetting. Cell. 2024;187(12):3072\u2013e8920.","journal-title":"Cell"},{"issue":"6137","key":"5006_CR32","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1234852","volume":"340","author":"T Sato","year":"2013","unstructured":"Sato T, Clevers H. Growing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications. Science. 2013;340(6137):1190\u20134.","journal-title":"Science"},{"issue":"1","key":"5006_CR33","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.stemcr.2017.11.004","volume":"10","author":"Y Takahashi","year":"2018","unstructured":"Takahashi Y, Sato S, Kurashima Y, Yamamoto T, Kurokawa S, Yuki Y, et al. A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids. Stem Cell Rep. 2018;10(1):314\u201328.","journal-title":"Stem Cell Rep"},{"issue":"4","key":"5006_CR34","doi-asserted-by":"publisher","first-page":"812","DOI":"10.3390\/cells10040812","volume":"10","author":"S Qiu","year":"2021","unstructured":"Qiu S, Li Y, Imakura Y, Mima S, Hashita T, Iwao T, et al. An Efficient Method for the Differentiation of Human iPSC-Derived Endoderm toward Enterocytes and Hepatocytes. Cells. 2021;10(4):812.","journal-title":"Cells"},{"issue":"2","key":"5006_CR35","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ydbio.2019.03.009","volume":"450","author":"L Hartl","year":"2019","unstructured":"Hartl L, Huelsz-Prince G, van Zon J, Tans SJ. Apical constriction is necessary for crypt formation in small intestinal organoids. Dev Biol. 2019;450(2):76\u201381.","journal-title":"Dev Biol"},{"issue":"6","key":"5006_CR36","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1007\/s10237-010-0280-0","volume":"10","author":"MR Nelson","year":"2011","unstructured":"Nelson MR, Howard D, Jensen OE, King JR, Rose FRAJ, Waters SL. Growth-induced buckling of an epithelial layer. Biomech Model Mechanobiol. 2011;10(6):883\u2013900.","journal-title":"Biomech Model Mechanobiol"},{"issue":"4","key":"5006_CR37","first-page":"640","volume":"32","author":"CJ Childs","year":"2024","unstructured":"Childs CJ, Poling HM, Chen K, Tsai Y-H, Wu A, Sweet CW, et al. Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature. bioRxiv. 2024;32(4):640\u201351.","journal-title":"bioRxiv"},{"issue":"4","key":"5006_CR38","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1038\/nm.2695","volume":"18","author":"S Yui","year":"2012","unstructured":"Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5\u2009+\u2009stem cell. Nat Med. 2012;18(4):618\u201323.","journal-title":"Nat Med"},{"issue":"43","key":"5006_CR39","doi-asserted-by":"publisher","first-page":"3879","DOI":"10.1093\/eurheartj\/ehy249","volume":"39","author":"D Mosqueira","year":"2018","unstructured":"Mosqueira D, Mannhardt I, Bhagwan JR, Lis-Slimak K, Katili P, Scott E, et al. CRISPR\/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur Heart J. 2018;39(43):3879\u201392.","journal-title":"Eur Heart J"},{"issue":"12","key":"5006_CR40","doi-asserted-by":"publisher","first-page":"10266","DOI":"10.3390\/ijms241210266","volume":"24","author":"S Cuevas-Oca\u00f1a","year":"2023","unstructured":"Cuevas-Oca\u00f1a S, Yang JY, Aushev M, Schlossmacher G, Bear CE, Hannan NRF, et al. A Cell-Based Optimised Approach for Rapid and Efficient Gene Editing of Human Pluripotent Stem Cells. Int J Mol Sci. 2023;24(12):10266.","journal-title":"Int J Mol Sci"},{"issue":"1","key":"5006_CR41","doi-asserted-by":"publisher","first-page":"015006","DOI":"10.1088\/1758-5090\/ab446e","volume":"12","author":"R Kim","year":"2019","unstructured":"Kim R, Attayek PJ, Wang Y, Furtado KL, Tamayo R, Sims CE, et al. An in vitro intestinal platform with a self-sustaining oxygen gradient to study the human gut\/microbiome interface. Biofabrication. 2019;12(1):015006.","journal-title":"Biofabrication"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-026-05006-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-026-05006-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-026-05006-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:49:08Z","timestamp":1778734148000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13287-026-05006-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5006"],"URL":"https:\/\/doi.org\/10.1186\/s13287-026-05006-4","relation":{},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"assertion":[{"value":"23 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal experiments were conducted under the overview of the University of Nottingham Animal Welfare and Ethical Review Body (AWERB) and authorised by UK Home Office Project Licence numbers PPL P435A9CF8 (project title: Pre-clinical cancer models for identifying and screening novel drug and imaging agents for cancer diagnosis and treatment, approval date: 30\/11\/2017) and PP5089113 (project title: The development and application of preclinical cancer models for identifying and screening novel drug and imaging agents for cancer diagnosis and treatment, approval date: 15\/06\/2023). hiPSC lines were approved and derived under University of Nottingham ethics committee number 09\/H0408\/74 with appropriate consent(project title: \u201cNew in vitro models of long QT syndrome by coupling induced pluripotency and cardiomyocyte differentiation\u201d; approval date: 07\/03\/2011). OSTI GI4380 hiPSCs were approved for use as part of the CORGI2 trial by the Oxford\/South Central Research Ethics Committee (17\/SC\/0079; project title: \u201cThe Identification and characterisation of Inherited Predispositions to Colorectal Tumours (CORGI) 2\u201d, approval date: 10\/03\/2017). All ethical regulations were followed throughout the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"182"}}