What is the evidence to support the presence of a multipotential precursor cell in the glandular epithelium?
M.M. Berenson (Salt Lake City)
Barrett's esophagus (BE) is an acquired metaplastic condition with genetic predisposition in which glandular epithelium replaces the normal stratified squamous tissue of the distal esophagus [1, 2]. Metaplasia of epithelial tissue is generally characterized by replacement of one differentiated tissue by a differently differentiated type. It may develop as a consequence of tissue regeneration accompanied by atypical differentiation . Epithelial cell differentiation is a multistep process. Each step is regulated by a variety of factors. The factors link cell proliferation and differentiation . Theoretically, metaplastic tissue has the potential to revert to normal .
The metaplastic epithelium of BE is composed of four histologic types:
- a junctional type consisting of mucous-secreting cells and glands indistinguishable from gastric cardiac mucosa;
- a fundic type resembling atrophic gastric glands containing parietal cells and chief cells;
- a specialized intestinal type characterized by a villous architecture, mucous-secreting glands, and goblet cells;
- an intermediate type with villiform columnar cells but no goblet cells, parietal cells, chief cells, Paneth's cells, or junctional type epithelial glands [6, 7]. These histologic types are randomly mixed in a mosaic that may contain all cell types of the stomach and small intestine, including neuroendocrine cells and Paneth's cells .
The cell of origin of the metaplastic tissue has not been directly established. Experimental animal studies by Wong et al.  and Bremner et al.  showed heterotopic columnar epithelial extensions or growth of gastric tissue into the distal esophagus after wounding or stripping of the mucosa immediately above the squamocolumnar border and creating esophageal reflux of gastroduodenal contents. Morphologic examination of the heterotopic tissue to detect the presence of atypism was not performed. It is conceivable that heterotopic gastric junctional mucosa could be modified to account for the other histologic types. However, it has now been established by Gillen et al.  that glandular epithelium can develop in denuded esophageal tissue separated from gastric junctional mucosa, precluding cephaled extension of the gastric mucosa. These investigators suggested that the glandular tissue originated from cells lining the ducts of the esophageal cardiac glands . The distal two-thirds of these ducts are comprised of columnar or cuboidal cells; the proximal, superficial one-third, is comprised of squamous cells. Histologic sections of regenerated columnar tissue showed direct continuity of the ducts and glandular tissue. Alternatively, the glandular tissue may be derived from primordial stem cells in the basal layer of the stratified squamous epithelium or from cells in the lamina propria that migrate to areas undergoing repair [13, 14].
The cell of origin of the glandular epithelium must account for a diverse array of morphological and functional phenotypes. Morphologic phenotypes include all cell types of the stomach and small intestine [6-8], colonic epithelial epitopes , pancreatic cells , neuroendocrine cells of the adult , and immature  gastrointestinal tract, a novel double muscularis mucosa , and a unique hybrid surface epithelial cell with microvilli, intercellular ridges and surface microridges . Functional phenotypes include variable mucins [21, 22], pepsinogens [23, 24], enzyme activities  and enzyme gene expression , cytokeratin profiles  and others [28-30]. It seems reasonable to suggest that only a primordial stem cell with the potential to differentiate along multiple pathways can account for these characteristics. The presence of stratified columnar and ciliated columnar tissue in the developing esophagus between weeks 1 to 16 of life indicates the multipotentiality of esophageal cells . Finally, restoration of squamous mucosa after ablation of Barrett's epithelium totally surrounded by glandular tissue provides evidence of a progenitor cell within the esophageal tissue that has the potential to differentiate normally .
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