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Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor
  1. Anna M Nicholson1,2,
  2. Trevor A Graham3,
  3. Ashley Simpson3,
  4. Adam Humphries2,
  5. Nicola Burch4,
  6. Manuel Rodriguez-Justo5,
  7. Marco Novelli5,
  8. Rebecca Harrison4,
  9. Nicholas A Wright3,
  10. Stuart A C McDonald2,
  11. Janusz A Jankowski1,2,4
  1. 1Department of Oncology, University of Oxford, Oxford, UK
  2. 2Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  3. 3Histopathology Laboratory, Cancer Research, London Research Institute, Lincolns Inn Fields, London, UK
  4. 4Digestive Diseases Centre University Hospitals of Leicester, Leicester, UK
  5. 5Department of Histopathology, University College London, London, UK
  1. Correspondence to Professor Janusz A Jankowski, Centre for Digestive Diseases, Blizard Institute for Cell and Molecular Science, 4 Newark Street, Whitechapel E1 2AT, UK; j.a.jankowski{at}qmul.ac.uk Dr Stuart AC McDonald, Centre for Digestive Diseases, Blizard Institute for Cell and Molecular Science, 4 Newark Street, Whitechapel E1 2AT, UK; s.a.mcdonald{at}qmul.ac.uk

Abstract

Background Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations.

Methods Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry.

Results The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 μm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett's metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett's metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett's metaplasia stem cells. Patches of clonally mutated Barrett's metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell.

Conclusion In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett's metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity.

  • Oesophagus
  • Barrett's metaplasia
  • clonality
  • mitochondrial DNA
  • stem cells
  • Barrett's oesophagus
  • colorectal adenomas
  • mathematical modelling
  • Barrett's carcinoma
  • microsatellite instability
  • carcinogenesis
  • colonic neoplasms
  • colonic polyps
  • colorectal cancer
  • histopathology
  • liver
  • gastrointestinal tract
  • molecular carcinogenesis
  • gastric adenocarcinoma
  • epithelial differentiation
  • gastrointestinal pathology
  • gastric carcinoma

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Footnotes

  • SACM and JAJ contributed equally to this manuscript.

  • Funding C548/A5675—CHOPIN—Chemoprevention of Premalignant Intestinal Neoplasia.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval 07/Q1604/17 Oxfordshire Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statements We are happy to share any data with any interested parties on request.

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