TY  - UNPB
N1  - 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.
Y1  - 2025/01/28/
AV  - restricted
EP  - 372
TI  - Organoid-based regenerative medicine technologies across regions and developmental stages of the gastrointestinal tract
A1  - Jones, Brendan Christopher
M1  - Doctoral
UR  - https://discovery.ucl.ac.uk/id/eprint/10203094/
PB  - UCL (University College London)
N2  - 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.
ID  - discovery10203094
ER  -