Stochastic homeostasis in human airway epithelium is achieved by neutral competition of basal cell progenitors
Vitor H Teixeira,
Parthiban Nadarajan,
Trevor A Graham,
Christodoulos P Pipinikas,
James M Brown,
Mary Falzon,
Emma Nye,
Richard Poulsom,
David Lawrence,
Nicholas A Wright,
Stuart McDonald,
Adam Giangreco,
Benjamin D Simons,
Sam M Janes
Affiliations
Vitor H Teixeira
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
Parthiban Nadarajan
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
Trevor A Graham
Histopathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom; Centre for Evolution and Cancer, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States
Christodoulos P Pipinikas
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
James M Brown
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
Mary Falzon
Department of Histopathology, University College Hospital London, London, United Kingdom
Emma Nye
Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom
Richard Poulsom
Histopathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom; Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
David Lawrence
Department of Cardiothoracic Surgery, The Heart Hospital, London, United Kingdom
Nicholas A Wright
Histopathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom; Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
Stuart McDonald
Histopathology Laboratory, Cancer Research UK London Research Institute, London, United Kingdom; Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom
Adam Giangreco
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
Benjamin D Simons
Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, United Kingdom; The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust–Medical Research Council Stem Cell Institute, University of Cambridge, United Kingdom
Sam M Janes
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom
Lineage tracing approaches have provided new insights into the cellular mechanisms that support tissue homeostasis in mice. However, the relevance of these discoveries to human epithelial homeostasis and its alterations in disease is unknown. By developing a novel quantitative approach for the analysis of somatic mitochondrial mutations that are accumulated over time, we demonstrate that the human upper airway epithelium is maintained by an equipotent basal progenitor cell population, in which the chance loss of cells due to lineage commitment is perfectly compensated by the duplication of neighbours, leading to “neutral drift” of the clone population. Further, we show that this process is accelerated in the airways of smokers, leading to intensified clonal consolidation and providing a background for tumorigenesis. This study provides a benchmark to show how somatic mutations provide quantitative information on homeostatic growth in human tissues, and a platform to explore factors leading to dysregulation and disease.
