Abstract
Pancreatic islet transplantation is an attractive treatment option for a subset of patients with Type 1 diabetes. However islet transplantation efficacy remains hampered by a number of factors, including the impaired quality of isolated islets available for transplantation and the loss of long-term islet function post transplantation. Harnessing the properties of multipotent mesenchymal stromal cells (MSCs), which can be derived from numerous clinically relevant post-natal tissues including adipose and pancreas, is currently under investigation for improving the survival of islet cells during culture and after transplantation. Amongst other beneficial properties, MSCs are known to provide a supportive micro-environmental niche via secretion of paracrine factors or deposition of extracellular matrix, making them excellent candidates to play the role of islet ‘helper’ cells for purposes of improving islet transplantation outcome.Preliminary studies conducted within the group demonstrated that co-transplantation of islets and MSCs improve the survival and function of engrafted islets post-transplantation, leading to overall improved outcomes of islet grafts in mouse models of Type 1 diabetes. The aims of this thesis were to investigate the mechanisms through which MSCs were exerting beneficial effects on islet function in vivo using in vitro co-culture methods and then to develop these findings into potential pre-transplant islet culture protocols with the aim of improving the function of isolated human islets available for transplantation. After deriving and characterising adipose MSCs (adipMSCs) from mouse tissue, it was demonstrated that direct cell-cell contact, between mouse islets and MSCs co-cultured in vitro was necessary for enhancing islet insulin secretory function compared to islets cultured alone, whereas the trophic factors secreted by the MSCs alone were not able to positively affect islet function. Additional co-culture studies also showed that the extracellular matrix (ECM) deposited by adipMSCs alone was able to improve the insulin secretory function of co-cultured islets, but not to the full extent of when MSCs were present. Through adopting a direct contact monolayer co-culture configuration for human islets and MSCs, it was also demonstrated that human adipMSCs improved the function of isolated human islets, more reproducibly than either human pancreatic MSCs (pMSCs) or human bone-marow MSCs (bmMSCs), supporting the use of adipMSCs in pre-transplant islet culture protocols. In summary adipMSCs enhanced the function of isolated islets through direct contact based mechanisms and warrant further investigation for use in clinical islet transplantation strategies, including the functional maintenance of isolated human islets in culture prior to transplantation.
| Date of Award | 2014 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Peter Jones (Supervisor) & Dusko Ilic (Supervisor) |