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Permanent link (DOI): https://doi.org/10.7939/R3FB0B

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Theses and Dissertations

Enhancing engraftment of islets of Langerhans and other cellular therapies for diabetes Open Access

Descriptions

Other title
Subject/Keyword
diabetes
islets of Langerhans
islet transplantation
stem cells
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
McCall, Michael David
Supervisor and department
Shapiro, James AM (Surgery)
Examining committee member and department
West, Lori (Pediatrics)
Anderson, Colin (Surgery)
Markmann, James (external)
Light, Peter (Pharmacology)
Department
Department of Surgery
Specialization

Date accepted
2011-08-31T22:13:04Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Islet transplantation is promising treatment for certain patients with type 1 diabetes who experience recurrent episodes of hypoglycemia with unawareness. One opportunity to improve on islet transplant outcomes and potentially broaden the recipient population, is to reduce the early post transplant islet loss. Another opportunity is to develop an alternative source of insulin-producing tissue; thus overcoming the need to rely on organ donation. Mouse islets are used throughout this thesis and their optimal isolation is a crucial step in many of the experiments contained herein. Histopaque provided the optimal isolation kinetics in addition to being the most cost-effective compound, as compared to dextran, iodixanol and ficoll. Apoptosis is the dominant mechanism by which islets are lost in the early post-transplant period. The caspase inhibitor IDN6556 reduced islet graft apoptosis and enhanced islet survival in both mouse and porcine models of islet transplantation. Cytokines, including TNFalpha and IL-1, contribute to islet toxicity in the early post-transplant period. As such, etanercept (TNFalpha inhibitor) has seen increased use in islet peri-transplant cocktails with minimal pre-clinical support. In our studies, the combination of etanercept, and anakinra (IL-1 receptor antagonist) led to improved islet engraftment as compared to either agent alone. One mechanism for this benefit was a significant reduction in apoptotic cells within the islet graft. We also attempted to enhance engraftment by utilizing resveratrol, a compound with known anti-oxidant and anti-inflammatory properties. Despite its benefit in other fields, it did not produce a benefit to islet engraftment over a wide dosing range. Stem cells are a promising alternative to cadaveric islet procurement. Herein we have demonstrated the ability to ship human embryonic stem cell-derived pancreatic cells (Cyt49) cells which developed pancreatic endocrine function after transplantation in immunodeficient mice. Although long-term teratoma formation was uncovered, this therapy has potential to overcome the reliance on organ donation and may broaden the diabetic recipient population. Overall, strategies to overcome early islet loss and the reliance on cadaveric donation of islets are presented here. The use of caspase inhibitors to prevent islet apoptosis is particularly encouraging and should be explored in clinical islet transplantation.
Language
English
DOI
doi:10.7939/R3FB0B
Rights
License granted by Michael McCall (mmccall@ualberta.ca) on 2011-08-31T03:23:48Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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