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

EBioMedicine
Craig StampLaura C Greaves

Abstract

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.

Citations

Sep 25, 2018·The Journal of Pathology·Darryl Shibata
Oct 26, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Yoshitatsu SeiStephen A Wank
Nov 14, 2019·Physical Biology·A J FendrikE Rotondo
Oct 28, 2019·Nature·Henry Lee-SixMichael R Stratton
May 20, 2020·Open Biology·Conor LawlessAmy E Vincent
Jan 15, 2020·Cold Spring Harbor Perspectives in Biology·Lemonia Chatzeli, Benjamin D Simons
Dec 6, 2019·Biogerontology·Julia C Whitehall, Laura C Greaves
Jun 30, 2019·Scientific Reports·Jorge Fernandez-de-Cossio-DiazAlexei Vazquez

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BETA
transgenic
biopsies
biopsy

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StereoInvestigator
MATLAB

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