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Title: Protection & regeneration of [beta]-cells : studies using the nod mouse
Author: Khoo, Cheen Peen
ISNI:       0000 0004 2682 936X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2009
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Diabetes is a chronic disease affecting approximately 250 million people. To date, transplantation-based therapy is the therapy of choice; however, its success is hampered by the scarcity of transplantable human material. An alternative strategy is the promotion of regeneration in the pancreas. Endothelial progenitor cells (EPCs), a subpopulation of bone marrow (BM) cells, can contribute to tissue repair in various pathological conditions via the formation of new blood vessels. In this thesis, I review and discuss the role and regenerative potential of EPCs in diabetes using non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D). Flow cytometry analyses of the EPC population in BM and blood of both diabetic and pre-diabetic NOD mice suggested that at the onset of diabetes, BM-derived EPCs are stimulated to enter the systemic circulation in response to signals from the pancreas. To further investigate the contribution of EPCs to β-cell regeneration, whole BM and cultured EPCs were transplanted into pre-diabetic and diabetic NOD mice soon after diabetes was diagnosed. Our data imply that BM cells from wild type mice administered before the onset of diabetes may have an effect in delaying β-cell destruction evidenced by glycaemic control, reduced inflammation and increased number of proliferating Ki-67+ Insulin+ cells. EPCs transplanted into early diabetic NOD mice had reduced inflammation and a higher survival rate compared to control mice that did not receive EPCs. I therefore believe that both BM and EPCs show great promise in regenerating the damaged pancreas of NOD mice. In addition to promoting endogenous β-cell regeneration using EPCs, I have investigated a strategy to protect β-cell death via apoptosis, using a protease peptide XG-102 developed by Xigen. Since apoptosis of β-cells is one of the putative mechanisms involved in the cascade of events leading to T1D, we tested XG-102, for prevention of β-cell loss in the NOD mouse. Treated mice had a larger number of islets and inflammation was less prevalent compared to control mice. Additionally, XG-102 treated mice showed better control of their blood glucose. In conclusion, both therapeutic strategies showed great promise in regenerating the damaged pancreas of NOD mice. While these strategies are still under further investigation, they offer encouragement in the quest for the treatment of early diabetes in the future.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine