The DOI matches its Crossref record; 30 of the 31 references it cites were found in a registry or an index.
Continuous Clonal Labeling Reveals Small Numbers of Functional Stem Cells in Intestinal Crypts and Adenomas
Open accessAbstract
Lineage-tracing approaches, widely used to characterize stem cell populations, rely on the specificity and stability of individual markers for accurate results. We present a method in which genetic labeling in the intestinal epithelium is acquired as a mutation-induced clonal mark during DNA replication. By determining the rate of mutation in vivo and combining this data with the known neutral-drift dynamics that describe intestinal stem cell replacement, we quantify the number of functional stem cells in crypts and adenomas. Contrary to previous reports, we find that significantly lower numbers of "working" stem cells are present in the intestinal epithelium (five to seven per crypt) and in adenomas (nine per gland), and that those stem cells are also replaced at a significantly lower rate. These findings suggest that the bulk of tumor stem cell divisions serve only to replace stem cell loss, with rare clonal victors driving gland repopulation and tumor growth.
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“Previous reports (Kozar et al., 2013) indicated that the number of ISCs and the number of stem cells replaced are age-independent by using a specific labeling technique of intestinal epithelial cells at a young age with a follow-up to 2 years.”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Kozar et al., 2013
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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
A human colon cancer cell capable of initiating tumour growth in immunodeficient mice
O'Brien, C. A., Pollett, A. F., Gallinger, S., & Dick, J. E. (2006) · Nature · doi:10.1038/nature05372 · Cited by 4,174
A Direct Measurement of the Radiation Sensitivity of Normal Mouse Bone Marrow Cells1
Till, J. E., & McCulloch, E. A. (2010) · Radiation Research · doi:10.1667/rrxx28.1 · Cited by 4,036
A Direct Measurement of the Radiation Sensitivity of Normal Mouse Bone Marrow Cells
Till, J. E., & McCulloch, E. A. (1961) · Radiation Research · doi:10.2307/3570892 · Cited by 3,848
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
Bmi1 is expressed in vivo in intestinal stem cells
Sangiorgi, E., & Capecchi, M. R. (2008) · Nature Genetics · doi:10.1038/ng.165 · Cited by 1,245
Heterogeneity in Cancer: Cancer Stem Cells versus Clonal Evolution
Shackleton, M. J., Quintana, E., Fearon, E. R., & Morrison, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.08.017 · Cited by 1,204
Cell intrinsic alterations underlie hematopoietic stem cell aging
Rossi, D. J., Bryder, D., Zahn, J. M., Ahlenius, H., Sonu, R., Wagers, A. J., & Weissman, I. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503280102 · Cited by 1,152 · cited 1×
“In hematopoiesis, this manifests as an increase in the number of phenotypic stem cells that are functionally impaired in respect to being able to support multilineage reconstitution on transplantation and in the number of cell divisions they can undergo (Rossi et al., 2005; Janzen et al., 2006; Nygren and Bryder, 2008…”
BackgroundLineage Tracing Reveals Lgr5 + Stem Cell Activity in Mouse Intestinal Adenomas
Schepers, A. G., Snippert, H. J. G., Stange, D. E., van den Born, M., van Es, J. H., van de Wetering, M., & Clevers, H. C. (2012) · Science · doi:10.1126/science.1224676 · Cited by 1,110
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106
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Swain, A. C. (2023) · doi:10.33540/1850
Buyan, M. I., Andrianova, N. V., & Plotnikov, E. Y. (2023) · Advances in Gerontology · doi:10.1134/s2079057024600344
Hustin, L., Conrad, C., Liu, C., Fuentealba, J. R., Menegatti, S., Shneer, S., Battistella, A., Tabarin, F., Weber, T., Amigorena, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.24.600543
Immune modulating stem cells represent a significant component of the immune system.Preprint
Karpenko, D. V. (2024) · doi:10.24108/preprints-3113266
Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality
Ferrandon, S., Kalady, M. F., & van Neerven, S. M. (2025) · Familial Cancer · doi:10.1007/s10689-025-00479-3
High-depth Whole Genome Sequencing of Single Human Colon Crypts Uncovers New View on Crypt ClonalityPreprint
Manojlovic, Z., Okitsu, C. Y., Okitsu, T., Wlodarczyk, J. R., Lieber, M. R., Loh, Y. H. E., & Hsieh, C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.24.677335
In vitro models of cell competition: current approaches and future directions
Bağlamış, S., Krawczyk, P. M., Vermeulen, L., van Neerven, S. M., & Lenos, K. (2026) · Oncogene · doi:10.1038/s41388-026-03751-7
Self-citationMechanisms of spontaneous loss of heterozygosity in adult stem cells
Al-Zoubi, L. (2020) · theses.fr (ABES) · doi:10.70675/c5a4265cz7577z45eeza66bz4aaa728ab681
Quantifying Haematopoietic Cell Dynamics
Hustin, L. (2022) · theses.fr (ABES) · doi:10.70675/48546646z0fa0z4e9bzb5a0zb1067f26721d
Epigenetic characterization of cellular pliancy in breast cancer
Benhassoun, R. (2024) · theses.fr (ABES) · doi:10.70675/0b1d39b2za3d7z4b26zb4b0zaafa77d5068a
Fluctuating DNA methylation sites encode colorectal tumour growth historyPreprint
Manojlović, V., Gabbutt, C., Shibata, D., & Noble, R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.04.730217
Lutsiv, T., Thompson, H. J., Fiehn, O., Gareau, M. G., Borowsky, A. D., Chen, B. H., & Hussan, H. (2026) · Gastro Hep Advances · doi:10.1016/j.gastha.2026.101102
Lorzadeh, A., Ye, G., Romero-Wolf, M., Quiloan, M. L., Sharma, S., Sanchez, E., & Jadhav, U. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.29.755502
Metadata
- Authors
- Kozar, S., Morrissey, E., Nicholson, A. M., van der Heijden, M., Zecchini, H. I., Kemp, R., Tavaré, S., Vermeulen, L., & Winton, D. J.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Winton, Douglas J.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 13
- Issue
- 5
- Pages
- 626-633
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2153618863
- Cited by
- 214
- References
- 31
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 8 · 2023: 17 · 2022: 18 · 2021: 16 · 2020: 18 · 2019: 17 · 2018: 21 · 2017: 15 · 2016: 24 · 2015: 19 · 2014: 21 · 2013: 4
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Cancer Research Institute
- Cancer Research UK (19556, 17044, 22310)
- KWF Kankerbestrijding
- Cancer Research UK Cambridge Institute, University of Cambridge
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- intestinal stem cells, DNA replication, intestinal crypts, intestinal adenoma, cancer stem cells, lineage tracing, neutral drift, intestinal epithelium, clonal expansion
- MeSH terms
- Adenoma, Animals, Intestinal Mucosa, Mice, Transgenic, Stem Cells, Neoplastic Stem Cells, Mice
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