FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2895949672> ?p ?o ?g. }

• W2895949672 endingPage "288" @default.
• W2895949672 startingPage "285" @default.
• W2895949672 abstract "Human induced pluripotent stem cells (iPSC) have been used to generate intestinal organoids that mimic key intestinal properties without the requirement for invasive procedures to obtain human tissues. The main protocols that have been described result in gut organoids that contain both intestinal epithelium as well as mesenchymal cells.1Spence J.R. et al.Nature. 2011; 470: 105-109Crossref PubMed Scopus (1281) Google Scholar, 2Forster R. et al.Stem Cell Reports. 2014; 2: 838-852Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar We have previously reported on human iPSC-derived intestinal organoids (iPSCo) that can be propagated in long-term culture that contain solely epithelial cells.3Forbester J.L. et al.Methods Mol Biol. 2016; (https://doi.org/10.1007/7651_2016_7)PubMed Google Scholar, 4Forbester J.L. et al.Infect Immun. 2015; 83 (2015): 2926-2934Crossref PubMed Scopus (80) Google Scholar, 5Hannan N.R.F. et al.Stem Cell Reports. 2013; 1: 293-306Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 6Kraiczy J. et al.Gut. 2019; 68: 49-61Crossref PubMed Scopus (86) Google Scholar, 7Kraiczy J. et al.Mucosal Immunol. 2016; 9: 647-658Crossref PubMed Scopus (21) Google Scholar A pure epithelial model offers unique opportunities to study epithelial cell intrinsic and cell-type–specific mechanisms. Among these cellular processes are epigenetic mechanisms such as DNA methylation, which acts as a key regulator of intestinal epithelial development and regional identity.1Spence J.R. et al.Nature. 2011; 470: 105-109Crossref PubMed Scopus (1281) Google Scholar, 7Kraiczy J. et al.Mucosal Immunol. 2016; 9: 647-658Crossref PubMed Scopus (21) Google Scholar The purpose of this study was to characterize iPSCo by comparing these cultures with primary purified intestinal epithelial cells (IECs). Intestinal epithelial organoid cultures were derived from at least 3 different lines of iPSCs according to the described protocol3Forbester J.L. et al.Methods Mol Biol. 2016; (https://doi.org/10.1007/7651_2016_7)PubMed Google Scholar, 4Forbester J.L. et al.Infect Immun. 2015; 83 (2015): 2926-2934Crossref PubMed Scopus (80) Google Scholar, 5Hannan N.R.F. et al.Stem Cell Reports. 2013; 1: 293-306Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar (see also Supplementary Figure 1), and showed a morphology comparable with mucosal biopsy-derived intestinal epithelial organoids. This was highlighted by the presence of epithelial cell adhesion molecules and epithelial polarization (Figure 1A). Furthermore, iPSCos were found to express several epithelial cell markers including E-cadherin (CDH1) and the intestinal stem cell marker LGR5 (Figure 1B). Immunofluorescent staining showed ubiquitous positivity for the enterocyte marker villin, with specific subsets of cells expressing mucin 2, chromogranin A, and lysozyme, markers associated with the epithelial cell subsets Goblet, enteroendocrine, and Paneth cells, respectively (Figure 1B and C). To further evaluate regional identity and the degree of developmental maturation of iPSCos, we performed DNA methylation and transcriptomic profiling using Illumina (Illumina, Cambridge, UK) Infinium bead arrays and RNA sequencing, respectively. We compared these genome-wide profiles with data sets we previously derived from purified IECs from mature terminal ileum and sigmoid colon (SC), as well as human fetal proximal gut and fetal distal gut (Supplementary Tables 1 and 2).6Kraiczy J. et al.Gut. 2019; 68: 49-61Crossref PubMed Scopus (86) Google Scholar Relative sample similarity based on multidimensional scaling indicated that iPSCos clustered more closely to mature colonic epithelium, both on an epigenetic (ie, DNA methylation) and transcriptomic level (Figure 2A and B). This was confirmed further by performing unsupervised, hierarchical clustering (Supplementary Figure 2), as well as differential DNA methylation and gene expression analyses. The latter showed that iPSCos had a greater number of significantly differentially methylated positions (adjusted P < .01) and differentially expressed genes (adjusted P < .01) in common with the SC than with the terminal ileum (Figure 2C, Supplementary Table 3). Given the overall similarity with pediatric sigmoid colon epithelium, we examined this relationship in more detail using mucosa-derived SC organoids (SCos) as an additional reference (Supplementary Figure 3A and B). We focused on the most significant differentially expressed genes (adjusted P < .01) between iPSCo and either purified IECs (SC purified epithelium) or organoids (SCo), respectively. Interestingly, some key small intestinal markers for Paneth cells (eg, α-defensins DEFA5 and DEFA6) were abundant in iPSCo, while several genes involved in innate defense (eg, IFI27, HCP5, PIGR) showed markedly lower expression levels (Figure 2D). This indicated that iPSCos may not reach the full level of differentiation into small or large intestinal epithelium as found in vivo. Thus, iPSCo models may require further optimization of the differentiation protocol to permit further maturation and regionalization. Studying the signaling pathways that could drive this maturation could offer unique insight into the processes involved in intestinal development. Together, our findings indicate that iPSC-derived human intestinal epithelial cell organoids more closely resemble mature colonic epithelium, which is in keeping with reports from other groups using alternative protocols to achieve distalization and maturation.8Múnera J.O. et al.Cell Stem Cell. 2017; 21: 51-64.e6Crossref PubMed Scopus (8) Google Scholar, 9Crespo M. et al.Nat Med. 2017; 23: 878-884Crossref PubMed Scopus (211) Google Scholar, 10Watson C.L. et al.Nat Med. 2014; 20: 1310-1314Crossref PubMed Scopus (386) Google Scholar However, using a genome-wide approach to validate the iPSCo model also uncovered distinct differences and incomplete regionalization of iPSC-derived organoids compared with human primary cells. These observations provide an ideal starting point to further investigate the factors required to model complete epithelial development in vitro. The authors would like to thank the members of the Zilbauer group who contributed to the original cohort, with special thanks to Komal M. Nayak, Kate J. Howell, Marco Gasparetto, Claire Lee, and Felicity Payne. The authors would like to express their gratitude to their collaborators Dr Bon-Kyoung Koo (Institute of Molecular Biotechnology, Vienna), Dr Oliver Stegle (European Bioinformatics Institute), Philip Rosenstiel (Christian-Albrechts University of Kiel), and Roger Barker (University of Cambridge). Furthermore, the authors are grateful to the clinical team of Paediatric Gastroenterology, Hepatology and Nutrition at Cambridge University Hospitals under Dr Robert Heuschkel, and all patients participating in this study. The authors would also like to thank the Wellcome Trust Sanger Institute Core Scientific Operations team for conducting transcriptome sequencing. Profiling data of iPSC-derived organoids is available at ArrayExpress under accession numbers E-MTAB-7289 (DNA methylation) and E-MTAB-7306 (RNA sequencing). Previously published data are accessible for DNA methylation under ArrayExpress accession number E-MTAB-4957; for RNA sequencing under ArrayExpress accession number E-MTAB-5015, or in the European Nucleotide Archive Study PRJEB15114 1.1Spence J.R. et al.Nature. 2011; 470: 105-109Crossref PubMed Scopus (1281) Google Scholar Download .pdf (.37 MB) Help with pdf files Supplementary Material" @default.
• W2895949672 created "2018-10-26" @default.
• W2895949672 creator A5019790992 @default.
• W2895949672 creator A5023167006 @default.
• W2895949672 creator A5026017416 @default.
• W2895949672 creator A5032122956 @default.
• W2895949672 creator A5035257699 @default.
• W2895949672 creator A5072480302 @default.
• W2895949672 date "2019-01-01" @default.
• W2895949672 modified "2023-10-16" @default.
• W2895949672 title "Genome-Wide Epigenetic and Transcriptomic Characterization of Human-Induced Pluripotent Stem Cell–Derived Intestinal Epithelial Organoids" @default.
• W2895949672 cites W1878295921 @default.
• W2895949672 cites W1984582197 @default.
• W2895949672 cites W2002513358 @default.
• W2895949672 cites W2024681578 @default.
• W2895949672 cites W2031522785 @default.
• W2895949672 cites W2036897871 @default.
• W2895949672 cites W2039521726 @default.
• W2895949672 cites W2043915076 @default.
• W2895949672 cites W2056040742 @default.
• W2895949672 cites W2080062510 @default.
• W2895949672 cites W2092742937 @default.
• W2895949672 cites W2101870168 @default.
• W2895949672 cites W2108234281 @default.
• W2895949672 cites W2134526812 @default.
• W2895949672 cites W2140729960 @default.
• W2895949672 cites W2143296478 @default.
• W2895949672 cites W2179438025 @default.
• W2895949672 cites W2207084272 @default.
• W2895949672 cites W2645361946 @default.
• W2895949672 cites W2684461861 @default.
• W2895949672 cites W2770282900 @default.
• W2895949672 doi "https://doi.org/10.1016/j.jcmgh.2018.10.008" @default.
• W2895949672 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6354438" @default.
• W2895949672 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30704978" @default.
• W2895949672 hasPublicationYear "2019" @default.
• W2895949672 type Work @default.
• W2895949672 sameAs 2895949672 @default.
• W2895949672 citedByCount "11" @default.
• W2895949672 countsByYear W28959496722019 @default.
• W2895949672 countsByYear W28959496722020 @default.
• W2895949672 countsByYear W28959496722021 @default.
• W2895949672 countsByYear W28959496722022 @default.
• W2895949672 countsByYear W28959496722023 @default.
• W2895949672 crossrefType "journal-article" @default.
• W2895949672 hasAuthorship W2895949672A5019790992 @default.
• W2895949672 hasAuthorship W2895949672A5023167006 @default.
• W2895949672 hasAuthorship W2895949672A5026017416 @default.
• W2895949672 hasAuthorship W2895949672A5032122956 @default.
• W2895949672 hasAuthorship W2895949672A5035257699 @default.
• W2895949672 hasAuthorship W2895949672A5072480302 @default.
• W2895949672 hasBestOaLocation W28959496721 @default.
• W2895949672 hasConcept C104317684 @default.
• W2895949672 hasConcept C107459253 @default.
• W2895949672 hasConcept C117717151 @default.
• W2895949672 hasConcept C141231307 @default.
• W2895949672 hasConcept C145103041 @default.
• W2895949672 hasConcept C150194340 @default.
• W2895949672 hasConcept C162317418 @default.
• W2895949672 hasConcept C190727270 @default.
• W2895949672 hasConcept C28328180 @default.
• W2895949672 hasConcept C2910924664 @default.
• W2895949672 hasConcept C31695470 @default.
• W2895949672 hasConcept C41091548 @default.
• W2895949672 hasConcept C54355233 @default.
• W2895949672 hasConcept C70721500 @default.
• W2895949672 hasConcept C86803240 @default.
• W2895949672 hasConcept C95444343 @default.
• W2895949672 hasConceptScore W2895949672C104317684 @default.
• W2895949672 hasConceptScore W2895949672C107459253 @default.
• W2895949672 hasConceptScore W2895949672C117717151 @default.
• W2895949672 hasConceptScore W2895949672C141231307 @default.
• W2895949672 hasConceptScore W2895949672C145103041 @default.
• W2895949672 hasConceptScore W2895949672C150194340 @default.
• W2895949672 hasConceptScore W2895949672C162317418 @default.
• W2895949672 hasConceptScore W2895949672C190727270 @default.
• W2895949672 hasConceptScore W2895949672C28328180 @default.
• W2895949672 hasConceptScore W2895949672C2910924664 @default.
• W2895949672 hasConceptScore W2895949672C31695470 @default.
• W2895949672 hasConceptScore W2895949672C41091548 @default.
• W2895949672 hasConceptScore W2895949672C54355233 @default.
• W2895949672 hasConceptScore W2895949672C70721500 @default.
• W2895949672 hasConceptScore W2895949672C86803240 @default.
• W2895949672 hasConceptScore W2895949672C95444343 @default.
• W2895949672 hasIssue "2" @default.
• W2895949672 hasLocation W28959496721 @default.
• W2895949672 hasLocation W28959496722 @default.
• W2895949672 hasLocation W28959496723 @default.
• W2895949672 hasLocation W28959496724 @default.
• W2895949672 hasLocation W28959496725 @default.
• W2895949672 hasLocation W28959496726 @default.
• W2895949672 hasOpenAccess W2895949672 @default.
• W2895949672 hasPrimaryLocation W28959496721 @default.
• W2895949672 hasRelatedWork W2522731802 @default.
• W2895949672 hasRelatedWork W2774001940 @default.
• W2895949672 hasRelatedWork W2793295809 @default.
• W2895949672 hasRelatedWork W2955027204 @default.
• W2895949672 hasRelatedWork W3031349637 @default.

• next