An assessment of stem cells, clonality and the inflammatory environment in Barrett's oesophagus

This thesis demonstrates a pulse-chase assay that describes the turnover of the .r J normal human oesophageal epithelium and Barretr~- metaplasia. to be approximately 11 days. This assay also identified the existence of label-retaining cells after 67 days within the basal layer of the human oesophagus and showed that these cells were epithelial in origin, capable of division yet are not frequently dividing. Furthermore, label-retaining cells were identified within the base of Barrett's glands and were also epithelial and primarily undifferentiated. This thesis suggests that these cells may represent a population of stem cells within the human oesophagus. Using mtDNA mutations as markers of clonal expansion, this thesis demonstrates the presence of a stem cell niche within the normal human oesophagus. Furthermore, clonal patches covering large areas of squamous epithelium were observed. In Barrett's oesophagus, partially-mutated glands were observed indicating that glands are maintained by multiple stem cells. Wholly-mutated Barrett's glands contain all the expected differentiated cell lineages; demonstrating multilineage differentiation from single stem cells. Patches of clonally-related Barrett's glands were also observed; indicating that glands can divide by fission. In one patient the squamous epithelium and the underlying glandular tissue were shown to be derived from a common progenitor cell. TNFa was shown to induce migration of Barrett's cells in vitro suggesting that the inflammatory environment contributes to the expansion of Barrett's lesion. Furthermore, data presented here shows that NSAIDs can act as TNFa inhibitors in the human oesophagus, by decreasing epithelial cell membrane TNFa levels in vivo. This suggests that anti-TNFa therapy may prevent further growth of Barrett's lesions. IIIEThOS - Electronic Theses Online ServiceGBUnited Kingdo