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The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands
  1. Danielle L Lavery1,
  2. Anna M Nicholson2,
  3. Richard Poulsom3,
  4. Rosemary Jeffery3,
  5. Alia Hussain1,
  6. Laura J Gay1,
  7. Janusz A Jankowski3,
  8. Sebastian S Zeki1,
  9. Hugh Barr4,
  10. Rebecca Harrison5,
  11. James Going6,
  12. Sritharan Kadirkamanathan7,
  13. Peter Davis7,
  14. Timothy Underwood8,
  15. Marco R Novelli9,
  16. Manuel Rodriguez–Justo9,
  17. Neil Shepherd10,
  18. Marnix Jansen11,
  19. Nicholas A Wright1,
  20. Stuart A C McDonald1
  1. 1Epithelial Stem Cell Group, Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  2. 2Stem Cell Biology of the Intestine Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
  3. 3Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  4. 4Department of Surgery, Gloucestershire Royal Hospital, Gloucestershire Royal Hospital, Gloucester, UK
  5. 5Department of Pathology, University Hospitals Leicester, Leicester, UK
  6. 6University of Glasgow, Institute of Cancer Sciences, Glasgow, UK
  7. 7Mid Essex Hospital Services NHS Trust, Broomfield Hospital, Chelmsford, UK
  8. 8Faculty of Medicine, University of Southampton, Southampton, UK
  9. 9Department of Histopathology, University College London, London, UK
  10. 10Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK
  11. 11Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands
  1. Correspondence to Dr Stuart McDonald, Centre for Tumour Biology, Barts Cancer Institute, Charterhouse Square, London EC1M 6BQ, UK; s.a.mcdonald{at}qmul.ac.uk

Abstract

Objective Barrett's oesophagus shows appearances described as ‘intestinal metaplasia’, in structures called ‘crypts’ but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands.

Methods Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry.

Results Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell.

Conclusions Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.

  • Barrett's Oesophagus
  • Gene Expression
  • Stem Cells
  • Trefoil Factors
  • Mucins

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