Journal
CELL REPORTS
Volume 8, Issue 4, Pages 940-947Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.019
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Funding
- Cancer Research UK
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Microsoft Research
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Dutch Cancer Research Foundation
- Wellcome Trust
- Higher Education Funding Council for England
- Cancer Research UK [14895] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/I017909/1] Funding Source: researchfish
- EPSRC [EP/I017909/1] Funding Source: UKRI
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Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a ''functional'' stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.
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