|dc.identifier.citation||Jawad, N. 2015. Exploring stem cell dynamics, clonal expansion and pseudopolyps in inflammatory bowel disease. Queen Mary University of London.||en_US
|dc.description.abstract||Inflammatory bowel disease (IBD) confers a high risk of development of colitis-associated
colorectal cancer in patients with extensive colitis. Crypt fission is a
mechanism of clonal expansion in the intestinal epithelium. Although fission is rare in
the normal colon, many crypts in IBD patients are in the process of fission.
Protumourigenic mutations can spread through the entire inflamed colon relatively
quickly indicating that stem cell dynamics are altered in IBD. Some patients with IBD
develop pseudopolyps as a result of mucosal ulceration and epithelial regeneration.
The aim of this PhD was to investigate the effect of inflammation on niche succession,
the crypt cycle and the expansion of clones in the IBD intestine. Pseudopolyps were
examined as potential sites for clonal expansion by determining the frequency of
mutated pseudopolyps and proliferative potential, and examining their microRNA
(miRNA) profile relative to inactive, active and dysplastic mucosa, and adenoma and
cancerous tissue. This thesis will show that crypt fission cycles in inflammatory bowel
diseased colon are protracted and that each stage of crypt fission appears to be slow.
Overall, clonally related adjacent IBD crypts seem to share a more recent common
ancestor than non-related IBD crypts, supporting increased crypt fission rates in IBD.
The proliferative drive induced by continuous inflammation and mucosal repair in
ulcerative colitis (UC) appears to promote the expansion of CCO-deficient patches.
Furthermore, niche succession appears to be faster in active IBD. Pseudopolyps are a
source of regeneration within the epithelium and, as shown here, have a faster
proliferative drive than background mucosa in IBD patients. Pseudopolyps are not
genetically inert and are a potential source of protumourigenic mutations in UC.
Hence, pseudopolyps are a potential reservoir within the inflamed epithelium where
mutations are harboured and where there is no competition from neighbouring
epithelium, as it has been denuded following previous inflammation. MiRNA
expression in pseudopolyps differs from that of UC-dysplasia and mucosa. In
particular, the MiR-29 family was downregulated in pseudopolyps, a miRNA family
that has been implicated in intestinal fibrosis formation in stricturing Crohn’s disease.
Pseudopolyps have been traditionally thought of as benign, genetically inert and
incidental findings characteristic of chronic inflammation. My research runs counter to
this view indicating an exciting paradigm shift in the way we consider pseudopolyps,
which may eventually alter the endoscopic management of these lesions in the future.||en_US
|dc.description.sponsorship||Bart’s and The London Charity; Medical
|dc.publisher||Queen Mary University of London||
|dc.title||Exploring stem cell dynamics, clonal expansion and pseudopolyps in inflammatory bowel disease.||en_US
|dc.rights.holder||The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author||