Jones, Brendan Christopher;
(2025)
Organoid-based regenerative medicine technologies across regions and developmental stages of the gastrointestinal tract.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Organoid-based regenerative medicine technologies across regions and developmental stages of the gastrointestinal tract |
| Language: | English |
| Additional information: | 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. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203094 |
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