Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts
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
Affiliations
Craig Stamp
LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Anze Zupanic
Swiss Federal Institute of Aquatic Science and Technology, Department of Environmental Toxicology, Dübendorf, Switzerland
Ashwin Sachdeva
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
Elizabeth A. Stoll
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Daryl P. Shanley
Institute of Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
John C. Mathers
LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
Thomas B.L. Kirkwood
Institute of Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
Rakesh Heer
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4AD, UK
Benjamin D. Simons
Cavendish Laboratory, Department of Physics, University of Cambridge, J.J. Thomson Avenue, Cambridge CB3 0HE, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Wellcome Trust/Medical Research Council SC Institute, Cambridge CB2 1QR, UK
Doug M. Turnbull
LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Laura C. Greaves
LLHW Centre for Ageing and Vitality, Newcastle University Institute for Ageing, The Medical School, Newcastle upon Tyne NE2 4HH, UK; Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Corresponding author at: LLHW Centre for Ageing and Vitality, Institute of Neuroscience, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
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
