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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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Batlle, E., & Clevers, H. (2017) · Nature Medicine · doi:10.1038/nm.4409 · Cited by 2,769
Variation in cancer risk among tissues can be explained by the number of stem cell divisions
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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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