The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands

Gut. 2014 Dec;63(12):1854-63. doi: 10.1136/gutjnl-2013-306508. Epub 2014 Feb 18.

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.

Keywords: Barrett's Oesophagus; Gene Expression; Mucins; Stem Cells; Trefoil Factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Barrett Esophagus* / metabolism
  • Barrett Esophagus* / pathology
  • Biomarkers, Tumor / metabolism
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Esophagus* / metabolism
  • Esophagus* / pathology
  • Gastric Mucosa / metabolism
  • Gene Expression Profiling
  • Goblet Cells / metabolism
  • Humans
  • Idoxuridine
  • Immunohistochemistry
  • Ki-67 Antigen / immunology
  • Mucin 5AC / metabolism*
  • Nucleic Acid Synthesis Inhibitors
  • Peptides / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Stem Cells / physiology*
  • Trefoil Factor-2
  • Trefoil Factor-3

Substances

  • Biomarkers, Tumor
  • Ki-67 Antigen
  • LGR5 protein, human
  • MUC5AC protein, human
  • Mucin 5AC
  • Nucleic Acid Synthesis Inhibitors
  • Peptides
  • Receptors, G-Protein-Coupled
  • TFF2 protein, human
  • TFF3 protein, human
  • Trefoil Factor-2
  • Trefoil Factor-3
  • Idoxuridine