“Islet equivalent” stem cells and diabetes
File(s)
Author(s)
Charif, Rawya
Type
Thesis
Abstract
Type I diabetes mellitus is a metabolic disorder caused by an autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans. Despite insulin treatment, diabetes results in the development of micro and macro-vascular complications that are associated with a high rate of morbidity and mortality. Curing diabetes would be the best treatment option for these patients. Pancreas transplantation is limited by the shortage of organ donors and by the high risk associated with this surgical procedure. Islets transplantation is a more recent non-invasive technique with a low risk of complications. It is however restricted by the shortage of organs and has variable success rates. Additionally, it is well established that after infusion of islets, a substantial percentage of them are lost immediately post-transplant through the instant blood-mediated inflammatory reaction. A promising option would be the use of stem cells as ‘islet equivalents’. These cells have the ability to proliferate and the capacity to differentiate into insulin-secreting cells leading to islet repair and regeneration of new beta cells. The cell source would not be limited and the cells could be transplanted in a non-invasive method.
This work examines the efficacy of two sources of stem cells in restoring euglycaemia in a diabetic animal model. It demonstrated the success of pancreas derived progenitor cells but not haematopoietic stem cells in reversing this diabetic phenotype. This work also examines whether these stem cells expressed tissue factor as a trigger for provoking coagulation leading to significant early cell loss. It demonstrated that both stem cell types are prothrombotic and that this effect can be mitigated by local treatment of these cells with anti-thrombin cytotopic agent. The results were however inconclusive whether this procoagulant effect was via TF-dependent or TF-independent mechanism.
Finally, this work includes the completion of a phase I trial demonstrating the safety and tolerability of the infusion of autologous expanded progeny of an adult CD34+ stem cell subset to patients with type I diabetes mellitus and a successful renal transplant. However, there was no convincing evidence to suggest efficacy of these cells in reducing insulin requirements in these diabetic patients.
This work examines the efficacy of two sources of stem cells in restoring euglycaemia in a diabetic animal model. It demonstrated the success of pancreas derived progenitor cells but not haematopoietic stem cells in reversing this diabetic phenotype. This work also examines whether these stem cells expressed tissue factor as a trigger for provoking coagulation leading to significant early cell loss. It demonstrated that both stem cell types are prothrombotic and that this effect can be mitigated by local treatment of these cells with anti-thrombin cytotopic agent. The results were however inconclusive whether this procoagulant effect was via TF-dependent or TF-independent mechanism.
Finally, this work includes the completion of a phase I trial demonstrating the safety and tolerability of the infusion of autologous expanded progeny of an adult CD34+ stem cell subset to patients with type I diabetes mellitus and a successful renal transplant. However, there was no convincing evidence to suggest efficacy of these cells in reducing insulin requirements in these diabetic patients.
Version
Open Access
Date Issued
2013-05
Date Awarded
2014-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Cook, Terence
Papalois, Vassilios
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)