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Intestinal label-retaining cells are secretory precursors expressing Lgr5
Abstract
The rapid cell turnover of the intestinal epithelium is achieved from small numbers of stem cells located in the base of glandular crypts. These stem cells have been variously described as rapidly cycling or quiescent. A functional arrangement of stem cells that reconciles both of these behaviours has so far been difficult to obtain. Alternative explanations for quiescent cells have been that they act as a parallel or reserve population that replace rapidly cycling stem cells periodically or after injury; their exact nature remains unknown. Here we show mouse intestinal quiescent cells to be precursors that are committed to mature into differentiated secretory cells of the Paneth and enteroendocrine lineage. However, crucially we find that after intestinal injury they are capable of extensive proliferation and can give rise to clones comprising the main epithelial cell types. Thus, quiescent cells can be recalled to the stem-cell state. These findings establish quiescent cells as an effective clonogenic reserve and provide a motivation for investigating their role in pathologies such as colorectal cancers and intestinal inflammation.
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“interconversion of reserve and active intestinal stem cell (ISC) populations has also been observed previously25,28–30.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [25]
Citations
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,893
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 12,082
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204
limma: Linear Models for Microarray Data
Smyth, G. K. (2005) · Statistics for Biology and Health · doi:10.1007/0-387-29362-0_23 · Cited by 5,796
Identification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687
Summaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,837
Bioinformatics and Computational Biology Solutions Using R and Bioconductor
Gentleman, R. C., Carey, V. J., Huber, W. K., Irizarry, R. A., & Dudoit, S. (2005) · Statistics in the health sciences · doi:10.1007/0-387-29362-0 · Cited by 3,470
Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Sato, T., van Es, J. H., Snippert, H. J., Stange, D. E., Vries, R. G., van den Born, M., Barker, N., Shroyer, N. F., van de Wetering, M., & Clevers, H. (2011) · Nature · doi:10.1038/nature09637 · Cited by 2,510
Snippert, H. J., van der Flier, L. G., Sato, T., van Es, J. H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A. M., van Rheenen, J., Simons, B. D., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.016 · Cited by 1,951
Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt
Potten, C. S., & Loeffler, M. (1990) · Development · doi:10.1242/dev.110.4.1001 · Cited by 1,793
Cheng, H., & Leblond, C. P. (1974) · American Journal of Anatomy · doi:10.1002/aja.1001410407 · Cited by 1,737
Coexistence of Quiescent and Active Adult Stem Cells in Mammals
Li, L., & Clevers, H. (2010) · Science · doi:10.1126/science.1180794 · Cited by 1,247
A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable
Tian, H., Biehs, B., Warming, S., Leong, K. G., Rangell, L. K., Klein, O. D., & de Sauvage, F. J. (2011) · Nature · doi:10.1038/nature10408 · Cited by 1,244
Bmi1 is expressed in vivo in intestinal stem cells
Sangiorgi, E., & Capecchi, M. R. (2008) · Nature Genetics · doi:10.1038/ng.165 · Cited by 1,243
He, X., Zhang, J., Tong, W.-G., Tawfik, O. W., Ross, J., Scoville, D. H., Tian, Q., Zeng, X., He, X., Wiedemann, L. M., et al. (2004) · Nature Genetics · doi:10.1038/ng1430 · Cited by 1,105
Dll1+ secretory progenitor cells revert to stem cells upon crypt damage
van Es, J. H., Sato, T., van de Wetering, M., Lyubimova, A., Nee, A. N. Y., Gregorieff, A., Sasaki, N., Zeinstra, L. M., van den Born, M., Korving, J., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2581 · Cited by 818
The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers
Muñoz, J., Stange, D. E., Schepers, A. G., van de Wetering, M., Koo, B., Itzkovitz, S., Volckmann, R., Kung, K. S., Köster, J., Radulescu, S., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.166 · Cited by 802
Interconversion Between Intestinal Stem Cell Populations in Distinct Niches
Takeda, N., Jain, R., LeBoeuf, M. R., Wang, Q., Lu, M. M., & Epstein, J. A. (2011) · Science · doi:10.1126/science.1213214 · Cited by 742
NCBI Reference Sequences: current status, policy and new initiatives
Pruitt, K. D., Tatusova, T., Klimke, W., & Maglott, D. R. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn721 · Cited by 736
Powell, A. E., Wang, Y., Li, Y., Poulin, E. J., Means, A. L., Washington, M. K., Higginbotham, J. N., Juchheim, A., Prasad, N., Levy, S. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.042 · Cited by 694
Intestinal Stem Cell Replacement Follows a Pattern of Neutral Drift
López‐García, C., Klein, A. M., Simons, B. D., & Winton, D. J. (2010) · Science · doi:10.1126/science.1196236 · Cited by 660
Self-citationIntestinal stem cells protect their genome by selective segregation of template DNA strands
Potten, C. S., Owen, G., & Booth, D. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.11.2381 · Cited by 633
Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells
Foudi, A., Hochedlinger, K., Van Buren, D., Schindler, J. W., Jaenisch, R., Carey, V., & Hock, H. (2009) · Nature Biotechnology · doi:10.1038/nbt.1517 · Cited by 586
Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells
Montgomery, R. K., Carlone, D. L., Richmond, C. A., Farilla, L., Kranendonk, M. E. G., Henderson, D. E., Baffour‐Awuah, N. Y., Ambruzs, D. M., Fogli, L. K., Algra, S. O., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013004108 · Cited by 566
PTEN-deficient intestinal stem cells initiate intestinal polyposis
He, X., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., Dirisina, R., Porter-Westpfahl, K. S., Hembree, M. J., Johnson, T., et al. (2007) · Nature Genetics · doi:10.1038/ng1928 · Cited by 427
Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling
Wong, V. W. Y., Stange, D. E., Page, M. E., Buczacki, S. J. A., Wabik, A., Itami, S., van de Wetering, M., Poulsom, R., Wright, N. A., Trotter, M. W. B., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2464 · Cited by 425
Self-citationVooijs, M., Jonkers, J., & Berns, A. J. M. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve064 · Cited by 354
Jensen, K. B., & Watt, F. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601886103 · Cited by 321
The segregation of DNA in epithelial stem cells
Potten, C. S., Hume, W. J., Reid, P. J., & Cairns, J. (1978) · Cell · doi:10.1016/0092-8674(78)90274-x · Cited by 313
Methods for the isolation of intact epithelium from the mouse intestine
Bjerknes, M., & Cheng, H. (1981) · The Anatomical Record · doi:10.1002/ar.1091990412 · Cited by 195
Regulation of Cre recombinase by ligand-induced complementation of inactive fragments
Jullien, N. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng131 · Cited by 177
Gracz, A. D., Ramalingam, S., & Magness, S. T. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00470.2009 · Cited by 161
Paneth Cells in Intestinal Homeostasis and Tissue Injury
Roth, S., Franken, P., Sacchetti, A., Kremer, A., Anderson, K. I., Sansom, O. J., & Fodde, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038965 · Cited by 150
Ireland, H., Houghton, C. A., Howard, L., & Winton, D. J. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20446 · Cited by 139
Self-citationDemidov, O. N., Timofeev, O. N., Lwin, H. N. Y., Kek, C., Appella, E., & Bulavin, D. V. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.05.020 · Cited by 114
Exon array data analysis using Affymetrix power tools and R statistical software
Lockstone, H. E. (2011) · Briefings in Bioinformatics · doi:10.1093/bib/bbq086 · Cited by 100
Campbell, S. J., Carlotti, F., Hall, P. A., Clark, A. J., & Wolf, C. R. (1996) · Journal of Cell Science · doi:10.1242/jcs.109.11.2619 · Cited by 69
Lewis, A., Segditsas, S., Deheragoda, M. G., Pollard, P. J., Jeffery, R. E., Nye, E. L., Lockstone, H. E., Belnoue-Davis, H. L., Clark, S. K., Stamp, G. W. H., et al. (2010) · Gut · doi:10.1136/gut.2009.193680 · Cited by 67
Characterization of a heat resistant ß-glucosidase as a new reporter in cells and mice
McCutcheon, S., Jones, K., Cumming, S. A., Kemp, R., Zecchini, H. I., SAUNDERS, J. C., Houghton, C., Howard, L., & Winton, D. J. (2010) · BMC Biology · doi:10.1186/1741-7007-8-89 · Cited by 13
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Clevers, H. C., Loh, K. M., & Nusse, R. (2014) · Science · doi:10.1126/science.1248012 · Cited by 1,386
Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration
Barker, N. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3721 · Cited by 1,424
Extracellular matrix: A dynamic microenvironment for stem cell niche
Gattazzo, F., Urciuolo, A., & Bonaldo, P. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.01.010 · Cited by 1,365
Single-cell messenger RNA sequencing reveals rare intestinal cell types
Grün, D., Lyubimova, A., Kester, L., Wiebrands, K., Basak, O., Sasaki, N., Clevers, H., & van Oudenaarden, A. (2015) · Nature · doi:10.1038/nature14966 · Cited by 1,234
Metadata
- Authors
- Buczacki, S. J. A., Zecchini, H. I., Nicholson, A. M., Russell, R., Vermeulen, L., Kemp, R., & Winton, D. J.
- Affiliations
- Cancer Research UK (GB)
- Corresponding author
- Winton, Douglas J.
- Venue
- Nature
- Published
- 2013-02-27
- Volume
- 495
- Issue
- 7439
- Pages
- 65-69
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2119059014
- Semantic Scholar
- 9cc05a3e71ae9af40d9b1e9b30a463e557747415
- Cited by
- 761
- References
- 39
- Citations by year
- 2026: 20 · 2025: 39 · 2024: 35 · 2023: 34 · 2022: 42 · 2021: 65 · 2020: 65 · 2019: 41 · 2018: 85 · 2017: 68 · 2016: 67 · 2015: 73 · 2014: 76 · 2013: 49
- FWCI
- 58.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Cancer Research UK (17044, 22310)
- Topics
- Health Sciences › Medicine › Gastroenterology › Digestive system and related health
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- label-retaining cells, Lgr5, Paneth cells, enteroendocrine cells, intestinal epithelial regeneration, intestinal injury, stem cell niche, lineage tracing, intestinal crypts, colorectal cancer, intestinal inflammation
- MeSH terms
- Animals, Cell Differentiation, Cell Division, Cell Separation, Clone Cells, Intestinal Neoplasms, Intestines, Regeneration, Staining and Labeling, Biomarkers, Cell Lineage, Paneth Cells, Multipotent Stem Cells, Receptors, G-Protein-Coupled, Mice, Stem Cell Niche
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