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

oleh: Craig Stamp, Anze Zupanic, Ashwin Sachdeva, Elizabeth A. Stoll, Daryl P. Shanley, John C. Mathers, Thomas B.L. Kirkwood, Rakesh Heer, Benjamin D. Simons, Doug M. Turnbull, Laura C. Greaves

Format: Article
Diterbitkan: Elsevier 2018-05-01

Deskripsi

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. Keywords: Intestine, Stem cell, Cell division, Mitochondria, Stem cell fate