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Title: Control of intestinal progenitor cell fate by the microenvironment
Author: Biswas, Sujata
ISNI:       0000 0004 7654 4821
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The conventional model of intestinal epithelial architecture describes a unidirectional tissue organisational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. I look at evidence to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment. Selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. The Wnt, BMP and Hedgehog pathways are explored in terms of epithelial and mesenchymal compartmentalisation and cross-talk, both in homeostasis and inflammation. Interactions between BMP and Hedgehog pathways are studied in vivo and in vitro. The BMP antagonist GREM1 is discussed, and the effect of a compartmental switch in its expression in humans (Hereditary Mixed Polyposis Syndrome) and in mouse models. This leads to ectopic crypts with supposed stem cell activity, and evidence for stem cell activity is interrogated using lineage tracing models and organoid cultures. The functionality of Sox9, a marker of ectopic crypts, is explored. An epithelial Sox9 knockout model is studied in terms of its effect on ectopic crypt formation. The role of Sox9 in intestinal restitution is also examined by using a chemical colitis model and a biopsy wounding model.
Supervisor: Leedham, Simon ; Tomlinson, Ian Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Colon (Anatomy)--Cancer--Genetic aspects