Barrett's oesophagus is a metaplastic pre-malignant disorder and the only established precursor lesion for oesophageal adenocarcinoma. Barrett's oesophagus develops when the normal stratified squamous epithelium of the lower oesophagus is replaced by a columnar lined mucosa with intestinal differentiation, usually in the context of chronic gastro-oesophageal reflux disease. The cellular and molecular mechanisms by which this metaplastic transformation occurs are poorly understood. Abnormal differentiation of multipotent stem cells in the squamous oesophagus, triggered by exposure to refluxate, is one potential mechanism. These stem cells could be located in the basal layer of the squamous oesophageal epithelium and/or in the neck region of the oesophageal submucosal gland ducts; however, their exact location and identification are still matter of discussion. Three-dimensional models combined with state-of-the-art imaging techniques are now applied to characterize the squamous epithelium in human oesophageal samples, and this could unveil essential information to identify these progenitor cells. Locating stem cells in human squamous oesophagus could have important implications for our understanding of Barrett's oesophagus and remarkably improve our future strategies for its prevention.

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