Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor.
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.


CONCLUSIONS
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.
Department of Oncology, University of Oxford, Oxford, UK.
Anna M
AM
Nicholson
Trevor A
TA
Graham
Ashley
A
Simpson
Adam
A
Humphries
Nicola
N
Burch
Manuel
M
Rodriguez-Justo
Marco
M
Novelli
Rebecca
R
Harrison
Nicholas A
NA
Wright
Stuart A C
SA
McDonald
Janusz A
JA
Jankowski
D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005819:Genetic Markers; D006801:Humans; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D017422:Sequence Analysis, DNA
D014408:Biomarkers, Tumor; D004272:DNA, Mitochondrial; D005819:Genetic Markers; D003576:Electron Transport Complex IV