{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:12:53Z","timestamp":1783008773857,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011386","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000}}],"reference-count":86,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/R016925\/1"],"award-info":[{"award-number":["BB\/R016925\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L01386X\/1"],"award-info":[{"award-number":["BB\/L01386X\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/W024144\/1"],"award-info":[{"award-number":["EP\/W024144\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/S01876X\/1"],"award-info":[{"award-number":["EP\/S01876X\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Organoids offer a powerful model to study cellular self-organisation, the growth of specific tissue morphologies <jats:italic>in-vitro<\/jats:italic>, and to assess potential medical therapies. However, the intrinsic mechanisms of these systems are not entirely understood yet, which can result in variability of organoids due to differences in culture conditions and basement membrane extracts used. Improving the standardisation of organoid cultures is essential for their implementation in clinical protocols. Developing tools to assess and predict the behaviour of these systems may produce a more robust and standardised biological model to perform accurate clinical studies. Here, we developed an algorithm to automate crypt-like structure counting on intestinal organoids in both <jats:italic>in-vitro<\/jats:italic> and <jats:italic>in-silico<\/jats:italic> images. In addition, we modified an existing two-dimensional agent-based mathematical model of intestinal organoids to better describe the system physiology, and evaluated its ability to replicate budding structures compared to new experimental data we generated. The crypt-counting algorithm proved useful in approximating the average number of budding structures found in our <jats:italic>in-vitro<\/jats:italic> intestinal organoid culture images on days 3 and 7 after seeding. Our changes to the <jats:italic>in-silico<\/jats:italic> model maintain the potential to produce simulations that replicate the number of budding structures found on days 5 and 7 of <jats:italic>in-vitro<\/jats:italic> data. The present study aims to aid in quantifying key morphological structures and provide a method to compare both <jats:italic>in-vitro<\/jats:italic> and <jats:italic>in-silico<\/jats:italic> experiments. Our results could be extended later to 3D <jats:italic>in-silico<\/jats:italic> models.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011386","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T17:28:40Z","timestamp":1692034120000},"page":"e1011386","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["In-silico and in-vitro morphometric analysis of intestinal organoids"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7415-3558","authenticated-orcid":true,"given":"Sandra","family":"Montes-Olivas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3897-5861","authenticated-orcid":true,"given":"Danny","family":"Legge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbie","family":"Lund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6009-7137","authenticated-orcid":true,"given":"Ann C.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7553-6358","authenticated-orcid":true,"given":"Lucia","family":"Marucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9848-1409","authenticated-orcid":true,"given":"Martin","family":"Homer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,14]]},"reference":[{"issue":"5","key":"pcbi.1011386.ref001","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/stem.3156","article-title":"Constitutive activity of a G protein-coupled receptor, DRD1, contributes to human cerebral organoid formation","volume":"38","author":"Q Wang","year":"2020","journal-title":"Stem Cells"},{"issue":"3","key":"pcbi.1011386.ref002","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.stem.2016.11.017","article-title":"Induction of Expansion and Folding in Human Cerebral Organoids","volume":"20","author":"Y Li","year":"2017","journal-title":"Cell Stem Cell"},{"issue":"20","key":"pcbi.1011386.ref003","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1039\/C8LC00206A","article-title":"Millifluidic culture improves human midbrain organoid vitality and differentiation","volume":"18","author":"E Berger","year":"2018","journal-title":"Lab on a Chip"},{"issue":"5","key":"pcbi.1011386.ref004","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium","volume":"141","author":"T Sato","year":"2011","journal-title":"Gastroenterology"},{"issue":"12","key":"pcbi.1011386.ref005","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/s41419-021-04376-2","article-title":"Transplantable programmed death ligand 1 expressing gastroids from gastric cancer prone Nfkb1\u2212\/\u2212 mice","volume":"12","author":"JT Low","year":"2021","journal-title":"Cell Death and Disease"},{"issue":"7828","key":"pcbi.1011386.ref006","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41586-020-2776-9","article-title":"Phenotypic landscape of intestinal organoid regeneration","volume":"586","author":"I Lukonin","year":"2020","journal-title":"Nature"},{"issue":"7574","key":"pcbi.1011386.ref007","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nature15695","article-title":"Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis","volume":"526","author":"M Takasato","year":"2015","journal-title":"Nature"},{"issue":"1","key":"pcbi.1011386.ref008","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13287-022-02752-z","article-title":"Modeling oxidative injury response in human kidney organoids","volume":"13","author":"A Przepiorski","year":"2022","journal-title":"Stem cell research and therapy"},{"key":"pcbi.1011386.ref009","doi-asserted-by":"crossref","DOI":"10.3389\/fmolb.2020.00020","article-title":"Routine Optical Clearing of 3D-Cell Cultures: Simplicity Forward","volume":"7","author":"E Nurnberg","year":"2020","journal-title":"Frontiers in Molecular Biosciences"},{"issue":"1","key":"pcbi.1011386.ref010","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41536-021-00134-2","article-title":"Regenerative medicine meets mathematical modelling: developing symbiotic relationships","volume":"6","author":"SL Waters","year":"2021","journal-title":"npj Regenerative Medicine"},{"key":"pcbi.1011386.ref011","doi-asserted-by":"crossref","first-page":"103071","DOI":"10.1016\/j.bspc.2021.103071","article-title":"Graph based method for cell segmentation and detection in live-cell fluorescence microscope imaging","volume":"71","author":"K Hajdowska","year":"2022","journal-title":"Biomedical Signal Processing and Control"},{"issue":"1","key":"pcbi.1011386.ref012","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41592-018-0253-2","article-title":"Evaluation of variability in human kidney organoids","volume":"16","author":"B Phipson","year":"2019","journal-title":"Nature Methods"},{"issue":"1","key":"pcbi.1011386.ref013","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1186\/s12859-019-2880-8","article-title":"Cell segmentation methods for label-free contrast microscopy: review and comprehensive comparison","volume":"20","author":"T Vicar","year":"2019","journal-title":"BMC Bioinformatics"},{"issue":"5","key":"pcbi.1011386.ref014","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3390\/jimaging8050127","article-title":"A Review of Watershed Implementations for Segmentation of Volumetric Images","volume":"8","author":"A Kornilov","year":"2022","journal-title":"Journal of Imaging"},{"issue":"7","key":"pcbi.1011386.ref015","doi-asserted-by":"crossref","first-page":"e2005970","DOI":"10.1371\/journal.pbio.2005970","article-title":"CellProfiler 3.0: Next-generation image processing for biology","volume":"16","author":"C McQuin","year":"2018","journal-title":"PLOS Biology"},{"key":"pcbi.1011386.ref016","doi-asserted-by":"crossref","DOI":"10.3389\/fnins.2021.629067","article-title":"Recent Trends and Perspectives in Cerebral Organoids Imaging and Analysis","volume":"15","author":"C Br\u00e9mond Martin","year":"2021","journal-title":"Frontiers in Neuroscience"},{"issue":"7244","key":"pcbi.1011386.ref017","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"T Sato","year":"2009","journal-title":"Nature"},{"issue":"October","key":"pcbi.1011386.ref018","first-page":"1","article-title":"Intestinal Morphogenesis in Development, Regeneration, and Disease: The Potential Utility of Intestinal Organoids for Studying Compartmentalization of the Crypt-Villus Structure","volume":"8","author":"O Kwon","year":"2020","journal-title":"Frontiers in Cell and Developmental Biology"},{"issue":"1","key":"pcbi.1011386.ref019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-55824-1","article-title":"An Efficient Intestinal Organoid System of Direct Sorting to Evaluate Stem Cell Competition in Vitro","volume":"9","author":"Y Fujimichi","year":"2019","journal-title":"Scientific Reports"},{"key":"pcbi.1011386.ref020","first-page":"245","volume-title":"The Impact of Food Bioactives on Health","author":"S Lukovac","year":"2015"},{"key":"pcbi.1011386.ref021","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3389\/fgene.2019.00873","article-title":"Mathematical Models of Organoid Cultures","volume":"10","author":"S Montes-Olivas","year":"2019","journal-title":"Frontiers in Genetics"},{"issue":"18","key":"pcbi.1011386.ref022","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1111\/j.1742-4658.2012.08646.x","article-title":"On the biomechanics of stem cell niche formation in the gut\u2014Modelling growing organoids","volume":"279","author":"P Buske","year":"2012","journal-title":"FEBS Journal"},{"issue":"2","key":"pcbi.1011386.ref023","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.ydbio.2017.10.013","article-title":"Linking stem cell function and growth pattern of intestinal organoids","volume":"433","author":"T Thalheim","year":"2018","journal-title":"Developmental Biology"},{"issue":"5","key":"pcbi.1011386.ref024","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1007\/s11538-017-0294-1","article-title":"Three-Dimensional Spatiotemporal Modeling of Colon Cancer Organoids Reveals that Multimodal Control of Stem Cell Self-Renewal is a Critical Determinant of Size and Shape in Early Stages of Tumor Growth","volume":"80","author":"H Yan","year":"2018","journal-title":"Bulletin of Mathematical Biology"},{"issue":"6","key":"pcbi.1011386.ref025","doi-asserted-by":"crossref","first-page":"e1002491","DOI":"10.1371\/journal.pbio.1002491","article-title":"Paneth Cell-Rich Regions Separated by a Cluster of Lgr5+ Cells Initiate Crypt Fission in the Intestinal Stem Cell Niche","volume":"14","author":"AJ Langlands","year":"2016","journal-title":"PLOS Biology"},{"issue":"12","key":"pcbi.1011386.ref026","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1016\/j.cpc.2009.07.019","article-title":"Chaste: A test-driven approach to software development for biological modelling","volume":"180","author":"J Pitt-Francis","year":"2009","journal-title":"Computer Physics Communications"},{"issue":"3","key":"pcbi.1011386.ref027","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1002970","article-title":"Chaste: An Open Source C++ Library for Computational Physiology and Biology","volume":"9","author":"GR Mirams","year":"2013","journal-title":"PLOS Computational Biology"},{"issue":"2","key":"pcbi.1011386.ref028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1005387","article-title":"Comparing individual-based approaches to modelling the self-organization of multicellular tissues","volume":"13","author":"JM Osborne","year":"2017","journal-title":"PLOS Computational Biology"},{"key":"pcbi.1011386.ref029","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2021.655862","article-title":"Modelling of Epithelial Growth, Fission and Lumen Formation During Embryonic Thyroid Development: A Combination of Computational and Experimental Approaches","volume":"12","author":"L Gonay","year":"2021","journal-title":"Frontiers in Endocrinology"},{"issue":"2","key":"pcbi.1011386.ref030","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s11538-017-0377-z","article-title":"A Multicellular Model of Intestinal Crypt Buckling and Fission","volume":"80","author":"AA Almet","year":"2018","journal-title":"Bulletin of Mathematical Biology"},{"issue":"6137","key":"pcbi.1011386.ref031","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1234852","article-title":"Growing Self-Organizing Mini-Guts from a Single Intestinal Stem Cell: Mechanism and Applications","volume":"340","author":"T Sato","year":"2013","journal-title":"Science"},{"key":"pcbi.1011386.ref032","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1109\/TIP.2012.2231087","article-title":"Generation of All-in-Focus Images by Noise-Robust Selective Fusion of Limited Depth-of-Field Images","volume":"22","author":"S Pertuz","year":"2013","journal-title":"IEEE Transactions on Image Processing"},{"issue":"1","key":"pcbi.1011386.ref033","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1038\/s41598-017-18815-8","article-title":"Automated brightfield morphometry of 3D organoid populations by OrganoSeg","volume":"8","author":"MA Borten","year":"2018","journal-title":"Scientific Reports"},{"issue":"2","key":"pcbi.1011386.ref034","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1039\/C4IB00236A","article-title":"An individual based computational model of intestinal crypt fission and its application to predicting unrestrictive growth of the intestinal epithelium","volume":"7","author":"C Pin","year":"2015","journal-title":"Integrative Biology (United Kingdom)"},{"issue":"1","key":"pcbi.1011386.ref035","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00285-009-0262-y","article-title":"A multiple timescale analysis of a mathematical model of the Wnt\/\u03b2-catenin signalling pathway","volume":"60","author":"GR Mirams","year":"2010","journal-title":"Journal of Mathematical Biology"},{"issue":"5","key":"pcbi.1011386.ref036","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/j.1365-2184.2009.00627.x","article-title":"An integrative computational model for intestinal tissue renewal","volume":"42","author":"IMM van Leeuwen","year":"2009","journal-title":"Cell Proliferation"},{"issue":"4","key":"pcbi.1011386.ref037","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1046\/j.0960-7722.2001.00216.x","article-title":"Cell migration and organization in the intestinal crypt using a lattice-free model","volume":"34","author":"FA Meineke","year":"2001","journal-title":"Cell proliferation"},{"issue":"3","key":"pcbi.1011386.ref038","doi-asserted-by":"crossref","first-page":"036001","DOI":"10.1088\/1478-3975\/6\/3\/036001","article-title":"A computational study of discrete mechanical tissue models","volume":"6","author":"P Pathmanathan","year":"2009","journal-title":"Physical Biology"},{"issue":"2","key":"pcbi.1011386.ref039","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2013.07.004","article-title":"The Intestinal Crypt, A Prototype Stem Cell Compartment","volume":"154","author":"H Clevers","year":"2013","journal-title":"Cell"},{"issue":"1","key":"pcbi.1011386.ref040","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1146\/annurev-nutr-082117-051644","article-title":"Nutritional Regulation of Intestinal Stem Cells","volume":"38","author":"S Alonso","year":"2018","journal-title":"Annual Review of Nutrition"},{"key":"pcbi.1011386.ref041","unstructured":"Kirk J. Traveling salesman problem\u2014genetic algorithm; 2020. https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/13680-traveling-salesman-problem-genetic-algorithm. Available from: https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/13680-traveling-salesman-problem-genetic-algorithm."},{"key":"pcbi.1011386.ref042","unstructured":"Manurung A. Elliptic fourier for shape analysis; 2022. https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/32800-elliptic-fourier-for-shape-analysis. Available from: https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/32800-elliptic-fourier-for-shape-analysis."},{"issue":"1","key":"pcbi.1011386.ref043","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s12915-021-00958-w","article-title":"Long-term live imaging and multiscale analysis identify heterogeneity and core principles of epithelial organoid morphogenesis","volume":"19","author":"L Hof","year":"2021","journal-title":"BMC Biology"},{"key":"pcbi.1011386.ref044","first-page":"1421","article-title":"Perspective: extending the utility of three-dimensional organoids by tissue clearing technologies","author":"EA Susaki","year":"2021","journal-title":"Frontiers in cell and developmental biology"},{"issue":"11","key":"pcbi.1011386.ref045","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1136\/thoraxjnl-2020-216368","article-title":"Rectal organoid morphology analysis (ROMA) as a promising diagnostic tool in cystic fibrosis","volume":"76","author":"S Cuyx","year":"2021","journal-title":"Thorax"},{"issue":"7332","key":"pcbi.1011386.ref046","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature09691","article-title":"Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro","volume":"470","author":"JR Spence","year":"2011","journal-title":"Nature"},{"issue":"4","key":"pcbi.1011386.ref047","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/nm.2695","article-title":"Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell","volume":"18","author":"S Yui","year":"2012","journal-title":"Nature medicine"},{"issue":"4","key":"pcbi.1011386.ref048","doi-asserted-by":"crossref","first-page":"e00159","DOI":"10.1128\/mBio.00159-12","article-title":"Stem cell-derived human intestinal organoids as an infection model for rotaviruses","volume":"3","author":"SR Finkbeiner","year":"2012","journal-title":"mBio"},{"issue":"1","key":"pcbi.1011386.ref049","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nm.4233","article-title":"Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system","volume":"23","author":"MJ Workman","year":"2017","journal-title":"Nature medicine"},{"issue":"7680","key":"pcbi.1011386.ref050","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature24489","article-title":"A single-cell survey of the small intestinal epithelium","volume":"551","author":"AL Haber","year":"2017","journal-title":"Nature"},{"issue":"5","key":"pcbi.1011386.ref051","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s11894-010-0130-3","article-title":"Intestinal Stem Cells","volume":"12","author":"S Umar","year":"2010","journal-title":"Current Gastroenterology Reports"},{"key":"pcbi.1011386.ref052","first-page":"1","volume-title":"Intestinal Stem Cell Niche. vol. 2 of Advances in Stem Cells and their Niches","author":"C Trentesaux","year":"2018"},{"key":"pcbi.1011386.ref053","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/bs.asn.2018.01.001","volume-title":"Intestinal Stem Cell Niche. vol. 2 of Advances in Stem Cells and their Niches","author":"SE Lee","year":"2018"},{"issue":"3","key":"pcbi.1011386.ref054","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.cell.2011.12.025","article-title":"Optimality in the development of intestinal crypts","volume":"148","author":"S Itzkovitz","year":"2012","journal-title":"Cell"},{"key":"pcbi.1011386.ref055","doi-asserted-by":"crossref","first-page":"7602951","DOI":"10.1155\/2017\/7602951","article-title":"Transit-Amplifying Cells in the Fast Lane from Stem Cells towards Differentiation","volume":"2017","author":"E Rangel-Huerta","year":"2017","journal-title":"Stem cells international"},{"issue":"6","key":"pcbi.1011386.ref056","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/j.cell.2006.03.011","article-title":"Stem Cells and Cancer: Two Faces of Eve","volume":"124","author":"MF Clarke","year":"2006","journal-title":"Cell"},{"key":"pcbi.1011386.ref057","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/bies.10028","article-title":"The intestinal epithelial stem cell","volume":"24","author":"E Marshman","year":"2002","journal-title":"BioEssays"},{"key":"pcbi.1011386.ref058","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev.physiol.010908.163145","article-title":"Stem cells, self-renewal, and differentiation in the intestinal epithelium","volume":"71","author":"LG van der Flier","year":"2009","journal-title":"Annual review of physiology"},{"key":"pcbi.1011386.ref059","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1038\/emboj.2011.26","article-title":"Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes","volume":"30","author":"AG Schepers","year":"2011","journal-title":"The EMBO Journal"},{"key":"pcbi.1011386.ref060","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41580-020-0278-0","article-title":"Cell fate specification and differentiation in the adult mammalian intestine","volume":"22","author":"J Beumer","year":"2021","journal-title":"Nature Reviews Molecular Cell Biology"},{"key":"pcbi.1011386.ref061","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.csbj.2020.05.022","article-title":"Software tools for 3D nuclei segmentation and quantitative analysis in multicellular aggregates","volume":"18","author":"F Piccinini","year":"2020","journal-title":"Computational and Structural Biotechnology Journal"},{"issue":"1","key":"pcbi.1011386.ref062","doi-asserted-by":"crossref","first-page":"11135","DOI":"10.1038\/s41598-018-29169-0","article-title":"A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models","volume":"8","author":"ME Boutin","year":"2018","journal-title":"Scientific Reports"},{"issue":"5","key":"pcbi.1011386.ref063","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1021\/acssynbio.0c00463","article-title":"Cheetah: a computational toolkit for cybergenetic control","volume":"10","author":"E Pedone","year":"2021","journal-title":"ACS Synthetic Biology"},{"issue":"4","key":"pcbi.1011386.ref064","doi-asserted-by":"crossref","first-page":"e1009879","DOI":"10.1371\/journal.pcbi.1009879","article-title":"Benchmarking of deep learning algorithms for 3D instance segmentation of confocal image datasets","volume":"18","author":"A Kar","year":"2022","journal-title":"PLoS computational biology"},{"issue":"4","key":"pcbi.1011386.ref065","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.bbrc.2018.10.181","article-title":"A novel morphometry system automatically assessing the growth and regeneration of intestinal organoids","volume":"506","author":"J Ren","year":"2018","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"18","key":"pcbi.1011386.ref066","doi-asserted-by":"crossref","DOI":"10.1242\/dev.199611","article-title":"MOrgAna: accessible quantitative analysis of organoids with machine learning","volume":"148","author":"N Gritti","year":"2021","journal-title":"Development"},{"issue":"1","key":"pcbi.1011386.ref067","doi-asserted-by":"crossref","first-page":"12479","DOI":"10.1038\/s41598-019-48874-y","article-title":"OrgaQuant: Human Intestinal Organoid Localization and Quantification Using Deep Convolutional Neural Networks","volume":"9","author":"T Kassis","year":"2019","journal-title":"Scientific Reports"},{"issue":"3","key":"pcbi.1011386.ref068","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.slasd.2022.03.004","article-title":"deepOrganoid: A brightfield cell viability model for screening matrix-embedded organoids","volume":"27","author":"RT Powell","year":"2022","journal-title":"SLAS Discovery"},{"issue":"1","key":"pcbi.1011386.ref069","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41598-021-04048-3","article-title":"A novel deep learning-based 3D cell segmentation framework for future image-based disease detection","volume":"12","author":"A Wang","year":"2022","journal-title":"Scientific Reports"},{"issue":"9","key":"pcbi.1011386.ref070","doi-asserted-by":"crossref","first-page":"e0138531","DOI":"10.1371\/journal.pone.0138531","article-title":"The Viral Mimetic Polyinosinic:Polycytidylic Acid Alters the Growth Characteristics of Small Intestinal and Colonic Crypt Cultures","volume":"10","author":"JM Davies","year":"2015","journal-title":"PLOS ONE"},{"key":"pcbi.1011386.ref071","doi-asserted-by":"crossref","first-page":"3710836","DOI":"10.1155\/2016\/3710836","article-title":"Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche","volume":"2016","author":"A Pastu\u0142a","year":"2016","journal-title":"Stem cells international"},{"key":"pcbi.1011386.ref072","first-page":"1600960","article-title":"IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis","author":"V Jeffery","year":"2017","journal-title":"The Journal of Immunology"},{"issue":"7","key":"pcbi.1011386.ref073","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/s41419-020-02790-6","article-title":"LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndrome","volume":"11","author":"H Wang","year":"2020","journal-title":"Cell Death and Disease"},{"issue":"8","key":"pcbi.1011386.ref074","doi-asserted-by":"crossref","DOI":"10.1242\/dev.194357","article-title":"Murine intestinal stem cells are highly sensitive to modulation of the T3\/TR\u03b11-dependent pathway","volume":"148","author":"M Godart","year":"2021","journal-title":"Development (Cambridge, England)"},{"issue":"5","key":"pcbi.1011386.ref075","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cels.2019.10.008","article-title":"Automated Design of Pluripotent Stem Cell Self-Organization","volume":"9","author":"ARG Libby","year":"2019","journal-title":"Cell Systems"},{"key":"pcbi.1011386.ref076","article-title":"Recent Trends and Perspectives in Cerebral Organoids Imaging and Analysis","volume":"15","author":"CB Martin","year":"2021","journal-title":"Frontiers in Neuroscience"},{"key":"pcbi.1011386.ref077","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/s41592-022-01508-0","article-title":"Automated high-speed 3D imaging of organoid cultures with multi-scale phenotypic quantification","volume":"19","author":"A Beghin","year":"2022","journal-title":"Nature Methods"},{"key":"pcbi.1011386.ref078","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.csbj.2019.12.015","article-title":"Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: Insights from an agent-based model","volume":"18","author":"D Ward","year":"2020","journal-title":"Computational and Structural Biotechnology Journal"},{"key":"pcbi.1011386.ref079","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13059-020-02048-6","article-title":"Systematic assessment of tissue dissociation and storage biases in single-cell and single-nucleus RNA-seq workflows","volume":"21","author":"E Denisenko","year":"2020","journal-title":"Genome Biology"},{"key":"pcbi.1011386.ref080","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/nbt.2859","article-title":"The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells","volume":"32","author":"C Trapnell","year":"2014","journal-title":"Nature Biotechnology"},{"key":"pcbi.1011386.ref081","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41586-018-0414-6","article-title":"RNA velocity of single cells","volume":"560","author":"GL Manno","year":"2018","journal-title":"Nature"},{"key":"pcbi.1011386.ref082","doi-asserted-by":"crossref","first-page":"942","DOI":"10.3389\/fbioe.2020.00942","article-title":"Computer-aided whole-cell design: taking a holistic approach by integrating synthetic with systems biology","volume":"8","author":"L Marucci","year":"2020","journal-title":"Frontiers in Bioengineering and Biotechnology"},{"issue":"11","key":"pcbi.1011386.ref083","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1021\/acssynbio.8b00235","article-title":"Regulation of Gene Expression and Signaling Pathway Activity in Mammalian Cells by Automated Microfluidics Feedback Control","volume":"7","author":"L Postiglione","year":"2018","journal-title":"ACS Synthetic Biology"},{"issue":"1","key":"pcbi.1011386.ref084","doi-asserted-by":"crossref","first-page":"4481","DOI":"10.1038\/s41467-019-12329-9","article-title":"A tunable dual-input system for on-demand dynamic gene expression regulation","volume":"10","author":"E Pedone","year":"2019","journal-title":"Nature Communications"},{"key":"pcbi.1011386.ref085","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.3389\/fbioe.2020.00705","article-title":"Toward Engineering Biosystems With Emergent Collective Functions","volume":"8","author":"TE Gorochowski","year":"2020","journal-title":"Frontiers in Bioengineering and Biotechnology"},{"issue":"5","key":"pcbi.1011386.ref086","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1021\/acssynbio.0c00463","article-title":"Cheetah: a computational toolkit for cybergenetic control","volume":"10","author":"E Pedone","year":"2021","journal-title":"ACS Synthetic Biology"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011386","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011386","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T17:42:25Z","timestamp":1693590145000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011386"}},"subtitle":[],"editor":[{"given":"Melissa L.","family":"Kemp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,14]]},"references-count":86,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011386","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1011386","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,14]]}}}