Moor, A. E., Harnik, Y., Ben-Moshe, S., Massasa, E. E., Rozenberg, M., Eilam, R., Bahar Halpern, K. & Itzkovitz, S. Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis. Cell 175, 1156â1167.e15 (2018).
Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39â53 (2021).
Bonis, V., Rossell, C. & Gehart, H. The intestinal epitheliumâfluid fate and rigid structure from crypt bottom to villus tip. Front. Cell Dev. Biol. 9, 661931 (2021).
Manco, R. et al. Clump sequencing exposes the spatial expression programs of intestinal secretory cells. Nat. Commun. 12, 3074 (2021).
Bahar Halpern, K. et al. Lgr5+ telocytes are a signaling source at the intestinal villus tip. Nat. Commun. 11, 1936 (2020).
Shoshkes-Carmel, M. et al. Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557, 242â246 (2018).
McCarthy, N. et al. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26, 391â402 (2020).
Valenta, T. et al. Wnt ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis. Cell Rep. 15, 911â918 (2016).
Sullivan, Z. A. et al. γδ T cells regulate the intestinal response to nutrient sensing. Science 371, eaba8310 (2021).
Bujko, A. et al. Transcriptional and functional profiling defines human small intestinal macrophage subsets. J. Exp. Med. 215, 441â458 (2017).
Brandtzaeg, P. et al. The B-cell system of human mucosae and exocrine glands. Immunol. Rev. 171, 45â87 (1999).
Beumer, J. et al. BMP gradient along the intestinal villus axis controls zonated enterocyte and goblet cell states. Cell Rep. 38, 110438 (2022).
Elmentaite, R. et al. Cells of the human intestinal tract mapped across space and time. Nature 597, 250â255 (2021).
Burclaff, J. et al. A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics. Cell. Mol. Gastroenterol. Hepatol. https://doi.org/10.1016/j.jcmgh.2022.02.007 (2022).
Holloway, E. M. et al. Mapping development of the human intestinal niche at single-cell resolution. Cell Stem Cell 28, 568â580 (2021).
Egozi, A. et al. Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis. PLoS Biol. 21, e3002124 (2023).
Fawkner-Corbett, D. et al. Spatiotemporal analysis of human intestinal development at single-cell resolution. Cell 184, 810â826 (2021).
Hickey, J. W. et al. Organization of the human intestine at single-cell resolution. Nature 619, 572â584 (2023).
Zilbauer, M. et al. A Roadmap for the Human Gut Cell Atlas. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-023-00784-1 (2023).
Forrest, A. R. R. et al. A promoter-level mammalian expression atlas. Nature 507, 462â470 (2014).
Bausch-Fluck, D. et al. The in silico human surfaceome. Proc. Natl Acad. Sci. USA 115, E10988âE10997 (2018).
Ashburner, M. et al. Gene Ontology: tool for the unification of biology. Nat. Genet. 25, 25â29 (2000).
Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27â30 (2000).
Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417â425 (2015).
Tuganbaev, T. et al. Diet diurnally regulates small intestinal microbiome-epithelial-immune homeostasis and enteritis. Cell 182, 1441â1459 (2020).
Harnik, Y. et al. Spatial discordances between mRNAs and proteins in the intestinal epithelium. Nat. Metab. 3, 1680â1693 (2021).
Kelly, J., Weir, D. G. & Feighery, C. Differential expression of HLA-D gene products in the normal and coeliac small bowel. Tissue Antigens 31, 151â160 (1988).
Scott, H., Solheim, B. G., Brandtzaeg, P. & Thorsby, E. HLA-DR-like antigens in the epithelium of the human small intestine. Scand. J. Immunol. 12, 77â82 (1980).
Mansbach, C. M. & Siddiqi, S. A. The biogenesis of chylomicrons. Annu. Rev. Physiol. 72, 315 (2010).
Mahmood Hussain, M. A proposed model for the assembly of chylomicrons. Atherosclerosis 148, 1â15 (2000).
Chung, J. et al. LDAF1 and seipin form a lipid droplet assembly complex. Dev. Cell 51, 551â563 (2019).
Hung, Y.-H., Carreiro, A. L. & Buhman, K. K. Dgat1 and Dgat2 regulate enterocyte triacylglycerol distribution and alter proteins associated with cytoplasmic lipid droplets in response to dietary fat. Biochim. Biophys. Acta 1862, 600â614 (2017).
Barker, H. G., Malm, J. R. & Reemtsma, K. Comparative fat and fatty acid intestinal absorption test utilizing radioiodine labeling; results in normal subjects. Proc. Soc. Exp. Biol. Med. 92, 471â474 (1956).
Lawen, A. & Lane, D. J. R. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid. Redox Signal. 18, 2473â2507 (2013).
Moor, A. E. et al. Global mRNA polarization regulates translation efficiency in the intestinal epithelium. Science 357, 1299â1303 (2017).
Zwick, R. K. et al. Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nat. Cell Biol. https://doi.org/10.1038/s41556-023-01337-z (2024).
Meran, L., Baulies, A. & Li, V. S. W. Intestinal stem cell niche: the extracellular matrix and cellular components. Stem Cells Int. 2017, e7970385 (2017).
Palikuqi, B. et al. Lymphangiocrine signals are required for proper intestinal repair after cytotoxic injury. Cell Stem Cell 29, 1262â1272 (2022).
Niec, R. E. et al. Lymphatics act as a signaling hub to regulate intestinal stem cell activity. Cell Stem Cell 29, 1067â1082 (2022).
Bernier-Latmani, J. et al. ADAMTS18+ villus tip telocytes maintain a polarized VEGFA signaling domain and fenestrations in nutrient-absorbing intestinal blood vessels. Nat. Commun. 13, 3983 (2022).
Santaolalla, R., Fukata, M. & Abreu, M. T. Innate immunity in the small intestine. Curr. Opin. Gastroenterol. 27, 125â131 (2011).
Moghaddami, M., Cummins, A. & Mayrhofer, G. Lymphocyte-filled villi: comparison with other lymphoid aggregations in the mucosa of the human small intestine. Gastroenterology 115, 1414â1425 (1998).
Crosnier, C., Stamataki, D. & Lewis, J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat. Rev. Genet. 7, 349â359 (2006).
Brügger, M. D. & Basler, K. The diverse nature of intestinal fibroblasts in development, homeostasis, and disease. Trends Cell Biol. 33, 834â849 (2023).
Chiquet-Ehrismann, R. Tenascins. Int. J. Biochem. Cell Biol. 36, 986â990 (2004).
Treuting, P. M., Arends, M. J. & Dintzis, S. M. in Comparative Anatomy and Histology (Second Edition) (eds. Treuting, P. M. et al.) Ch. 11, 191â211 (Academic, 2018). https://doi.org/10.1016/B978-0-12-802900-8.00011-7.
Subiran Adrados, C., Yu, Q., Bolaños Castro, L. A., Rodriguez Cabrera, L. A. & Yun, M. H. Salamander-Eci: an optical clearing protocol for the three-dimensional exploration of regeneration. Dev. Dyn. 250, 902â915 (2021).
Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352â356 (2017).
Ben-Moshe, S. & Itzkovitz, S. Spatial heterogeneity in the mammalian liver. Nat. Rev. Gastroenterol. Hepatol. https://doi.org/10.1038/s41575-019-0134-x (2019).
Trautmann, A. Extracellular ATP in the immune system: more than just a âdanger signalâ. Sci. Signal. 2, pe6 (2009).
Mabley, J. G. et al. Inosine reduces inflammation and improves survival in a murine model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G138âG144 (2003).
Liu, T. et al. ADAMDEC1 promotes skin inflammation in rosacea via modulating the polarization of M1 macrophages. Biochem. Biophys. Res. Commun. 521, 64â71 (2020).
OâShea, N. R. et al. Critical role of the disintegrin metalloprotease ADAM-like decysin-1 [ADAMDEC1] for intestinal immunity and inflammation. J. Crohns Colitis 10, 1417â1427 (2016).
Matsumoto, T. et al. Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation. Gut 50, 402â404 (2002).
Snover, D. C. Update on the serrated pathway to colorectal carcinoma. Hum. Pathol. 42, 1â10 (2011).
Rubio, C. A. Serrated adenoma of the duodenum. J. Clin. Pathol. 57, 1219â1221 (2004).
Lyubimova, A. et al. Single-molecule mRNA detection and counting in mammalian tissue. Nat. Protoc. 8, 1743â1758 (2013).
Preibisch, S., Saalfeld, S. & Tomancak, P. Globally optimal stitching of tiled 3D microscopic image acquisitions. Bioinformatics 25, 1463â1465 (2009).
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676â682 (2012).
Bagnoli, J. W. et al. Sensitive and powerful single-cell RNA sequencing using mcSCRB-seq. Nat. Commun. 9, 2937 (2018).
Kohen, R. et al. UTAP: User-friendly Transcriptome Analysis Pipeline. BMC Bioinform. 20, 154 (2019).
Elinger, D., Gabashvili, A. & Levin, Y. Suspension trapping (S-Trap) is compatible with typical protein extraction buffers and detergents for bottom-up proteomics. J. Proteome Res. 18, 1441â1445 (2019).
Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367â1372 (2008).
Gu, Z. Complex heatmap visualization. iMeta 1, e43 (2022).
Gu, Z., Gu, L., Eils, R., Schlesner, M. & Brors, B. circlize Implements and enhances circular visualization in R. Bioinform. Oxf. Engl. 30, 2811â2812 (2014).
Ni, Z. et al. SpotClean adjusts for spot swapping in spatial transcriptomics data. Nat. Commun. 13, 2971 (2022).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573â3587 (2021).
Bankhead, P. et al. QuPath: open source software for digital pathology image analysis. Sci. Rep. 7, 16878 (2017).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B 57, 289â300 (1995).
Cunningham, F. et al. Ensembl 2022. Nucleic Acids Res. 50, D988âD995 (2022).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545â15550 (2005).
CaliÅski, T. & Harabasz, J. A dendrite method for cluster analysis. Commun. Stat. 3, 1â27 (1974).
Stringer, C., Wang, T., Michaelos, M. & Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 18, 100â106 (2021).
Pachitariu, M. & Stringer, C. Cellpose 2.0: how to train your own model. Nat. Methods 19, 1634â1641 (2022).
Hickey, J. W., Tan, Y., Nolan, G. P. & Goltsev, Y. Strategies for accurate cell type identification in CODEX multiplexed imaging data. Front. Immunol. 12, 727626 (2021).
Levine, J. H. et al. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Cell 162, 184â197 (2015).
Ramilowski, J. A. et al. A draft network of ligand-receptor-mediated multicellular signalling in human. Nat. Commun. 6, 7866 (2015).
Shannon, C. E. The mathematical theory of communication. 1963. MD Comput. 14, 306â317 (1997).
Harnik, Y. et al. Spatial transcriptomics data for âA spatial expression atlas of the adult human proximal small intestineâ. Zenodo https://doi.org/10.5281/zenodo.10715015 (2024).
Harnik, Y. et al. Human villus zonation segmental tables for âA spatial expression atlas of the adult human proximal small intestineâ. Zenodo https://doi.org/10.5281/zenodo.11490477 (2024).
Harnik, Y. et al. LCM RNA-seq and proteomics raw data for âA spatial expression atlas of the adult human proximal small intestineâ. Zenodo https://doi.org/10.5281/zenodo.10715015 (2024).
Harnik, Y. et al. CODEX data for âA spatial expression atlas of the adult human proximal small intestineâ. Zenodo https://doi.org/10.5281/zenodo.10724499 (2024).
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
Wang, Y. et al. Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides. Nat. Commun. 14, 5093 (2023).
Hortsch, M. The Michigan Histology website as an example of a free anatomical resource serving learners and educators worldwide. Anat. Sci. Educ. 16, 363â371 (2023).