%0 Thesis
%9 Doctoral
%A Jones, Brendan Christopher
%B Developmental Biology and Cancer
%D 2025
%F discovery:10203094
%I UCL (University College London)
%P 372
%T Organoid-based regenerative medicine technologies across regions and developmental stages of the gastrointestinal tract
%U https://discovery.ucl.ac.uk/id/eprint/10203094/
%X Regenerative medicines have the potential to produce personalised therapies  by combining knowledge of stem cell biology with biomedical engineering. To  realise this potential in the gastrointestinal (GI) tract, normal development of  the GI epithelium and its response to injury must be understood. Epithelial  organoids derived from different regions of the GI tract and across  developmental time are a valuable human-specific in vitro system to  understand development, homeostasis, and injury, and could be a source of  cells for therapy when combined with an appropriate delivery method.  In this work, a technique for surgical mucosectomy of the mouse colon was  developed, that successfully left an intact vascularised neuromuscular coat  onto which intestinal organoid-based mucosal grafts could be delivered. The  aim was to ‘intestinalise’ the colon for treatment of short bowel syndrome.  When this project was forced to close by SARS-CoV-2 pandemic, the  technique’s components were feasible but high mortality in live mice  necessitates further optimisation of the model.  For the first time, this work describes human foetal and paediatric epithelial  gastric organoids (GOs), including gastric region-specific GOs. GOs were  reliably derived, even from sub-centimetre endoscopic biopsies, were  exponentially expandable and genetically stable in culture, and retained  memory of their developmental stage and region of derivation. GOs with  reversed cellular polarity were used to model SARS-CoV-2 infection in the  gastric epithelium, demonstrating age-related susceptibility (greatest in late  foetal and paediatric GOs) associated with induction of interferon stimulated  genes but minimal expression of interferons. Floating co-culture of fundus,  body, and antrum GOs in custom mini wells allowed GOs to self-organise into  multi-region models of the stomach. This model resulted in a broader diversity  of differentiated cell types and greater transcriptional similarity to native tissue,  increasing the fidelity of the in vitro gastric epithelial model beyond what had  been achieved to date.
%Z Copyright © The Author 2025.  Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/).  Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.  Access may initially be restricted at the author’s request.