Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.
Elsevier (Cell Press)
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Baker, A., Cereser, B., Melton, S., Fletcher, A., Rodriguez-Justo, M., Tadrous, P., Humphries, A., et al. (2014). Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.. Cell Reports, 8 (4), 940-947. https://doi.org/10.1016/j.celrep.2014.07.019
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.
This study was supported by Cancer Research UK (to A.-M.B. and N.A.W.), the Medical Research Council (to B.C. and S.A.C.M.), the Engineering and Physical Sciences Research Council (to A.G.F.), Microsoft Research (to A.G.F.), the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.R.J.), the Dutch Cancer Research Foundation (to M.J.), the Wellcome Trust (to B.D.S.), and Higher Education Funding Council for England (to T.A.G.).
Wellcome Trust (098357/Z/12/Z)
Wellcome Trust (092096/Z/10/Z)
External DOI: https://doi.org/10.1016/j.celrep.2014.07.019
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296565
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/