Tullie, Lucinda;
(2025)
Engineering intestinal mucosal grafts for modelling and transplantation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Intestinal tissue engineering is an evolving field which combines stem cell and developmental biology, material science and bioengineering. It aims to address an unmet clinical need in the treatment of short bowel syndrome as well as providing innovative in vitro modelling of gastro-intestinal development and disease. The aim of the PhD project was to generate an innovative intestinal mucosal graft as a regenerative approach for short bowel syndrome and for use in intestinal modelling. Here we demonstrate the feasibility of engineering small intestinal mucosal sheets using GMP compliant compressed collagen scaffold. Via maturation with air liquid interface (ALI) culture, these sheets demonstrate a differentiated functional epithelium with rudimental crypt-villus morphology, emulating that seen in native small intestine. This functional epithelial layer could be generated in vitro without supporting fibroblasts. Mucosal sheets were used for ex vivo intestinal modelling of the intestinal apicomplexan parasite Cryptosporidium, with “organoid only” sheets supporting its propagation in vitro. By engineering sheets with organoids and colorectal cancer associated fibroblasts, epithelial mesenchymal interactions in the colorectal tumour microenvironment were also modelled, revealing paracrine signalling which shaped epithelial morphology. Finally, engineered mucosal sheets implanted in vivo in heterotopic (subcutaneous) and orthotopic (serosal) transplantation models showed graft survival of up to 6 weeks. Orthotopic transplantation yielded superior differentiation of grafts when compared with heterotopic transplantation, suggesting that the intestinal microenvironment may have a key role in supporting epithelial maturation. Neither fibroblast seeding in the mucosal sheets nor ALI culture were required for successful in vivo engraftment with functional differentiation. This has translational impact by reducing number of cell types and shortening the engineering complexity and time. Preliminary data on colonic mucosal removal showed that mechanical mucosectomy via incision may be a viable option to retain neuromuscular function. Future work is to apply these grafts for mucosal repurposing in colon.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Engineering intestinal mucosal grafts for modelling and transplantation |
| Open access status: | An open access version is available from UCL Discovery |
| 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 Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences 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/10211156 |
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