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Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts

Lookup NU author(s): Dr Craig Stamp, Dr Anze Zupanic, Ashwin Sachdeva, Dr Elizabeth Stoll, Dr Daryl Shanley, Professor John Mathers, Emeritus Professor Thomas Kirkwood, Dr Rakesh Heer, Professor Doug Turnbull, Dr Laura Greaves

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018 The Authors Stem cell (SC) dynamics within the human colorectal crypt SC niche remain poorly understood, with previous studies proposing divergent hypotheses on the predominant mode of SC self-renewal and the rate of SC replacement. Here we use age-related mitochondrial oxidative phosphorylation (OXPHOS) defects to trace clonal lineages within human colorectal crypts across the adult life-course. By resolving the frequency and size distribution of OXPHOS-deficient clones, quantitative analysis shows that, in common with mouse, long-term maintenance of the colonic epithelial crypt relies on stochastic SC loss and replacement mediated by competition for limited niche access. We find that the colonic crypt is maintained by ~5 effective SCs. However, with a SC loss/replacement rate estimated to be slower than once per year, our results indicate that the vast majority of individual SC divisions result in asymmetric fate outcome. These findings provide a quantitative platform to detect and study deviations from human colorectal crypt SC niche homeostasis during the process of colorectal carcinogenesis.


Publication metadata

Author(s): Stamp C, Zupanic A, Sachdeva A, Stoll EA, Shanley DP, Mathers JC, Kirkwood TBL, Heer R, Simons BD, Turnbull DM, Greaves LC

Publication type: Article

Publication status: Published

Journal: EBioMedicine

Year: 2018

Volume: 31

Pages: 166-173

Print publication date: 01/05/2018

Online publication date: 25/04/2018

Acceptance date: 19/04/2018

Date deposited: 04/06/2018

ISSN (electronic): 2352-3964

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.ebiom.2018.04.017

DOI: 10.1016/j.ebiom.2018.04.017


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