title: The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.
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.
authors.affiliation: Epithelial 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.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Lavery
authors.affiliation: Stem Cell Biology of the Intestine Laboratory, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nicholson
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Richard
authors.identifier: http://orcid.org/0000-0001-8567-3543
authors.initials: R
authors.lastname: Poulsom
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.affiliation: Epithelial 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.
authors.forename: Alia
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Epithelial 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.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gay
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Jankowski
authors.affiliation: Epithelial 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.
authors.forename: Sebastian S
authors.initials: SS
authors.lastname: Zeki
authors.affiliation: Department of Surgery, Gloucestershire Royal Hospital, Gloucestershire Royal Hospital, Gloucester, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Barr
authors.affiliation: Department of Pathology, University Hospitals Leicester, Leicester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.affiliation: University of Glasgow, Institute of Cancer Sciences, Glasgow, UK.
authors.forename: James
authors.initials: J
authors.lastname: Going
authors.affiliation: Mid Essex Hospital Services NHS Trust, Broomfield Hospital, Chelmsford, UK.
authors.forename: Sritharan
authors.initials: S
authors.lastname: Kadirkamanathan
authors.affiliation: Mid Essex Hospital Services NHS Trust, Broomfield Hospital, Chelmsford, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Davis
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Underwood
authors.affiliation: Department of Histopathology, University College London, London, UK.
authors.forename: Marco R
authors.initials: MR
authors.lastname: Novelli
authors.affiliation: Department of Histopathology, University College London, London, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Shepherd
authors.affiliation: Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Epithelial 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.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.affiliation: Epithelial 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.
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
mesh_terms: D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling; D020397:Goblet Cells / Q000378:metabolism; D006801:Humans; D007065:Idoxuridine; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000276:immunology; D055271:Mucin 5AC / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors; D010455:Peptides / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C116884:LGR5 protein, human; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D019384:Nucleic Acid Synthesis Inhibitors; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; C000604007:TFF2 protein, human; C082495:TFF3 protein, human; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D007065:Idoxuridine
keywords: Barrett's Oesophagus; Gene Expression; Mucins; Stem Cells; Trefoil Factors