Journal
CELL TRANSPLANTATION
Volume 22, Issue 2, Pages 253-266Publisher
SAGE PUBLICATIONS INC
DOI: 10.3727/096368912X647180
Keywords
Hypoxia-inducible factor-1 alpha (HIP-l alpha); beta-Cell function; Islet transplantation; Deferoxamine (DFO); Diabetes; Hypoxia
Funding
- Juvenile Diabetes Research Foundation (JDRF)
- National Health and Medical Research Council (NHMRC) of Australia
- Diabetes Australia Research Trust (DART)
- L'Oreal Australian Women in Science Fellowship
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A high proportion of beta-cells die within days of islet transplantation. Reports suggest that induction of hypoxia-inducible factor-l alpha (HIF-1 alpha) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-l alpha protects beta-cells during transplantation. Transplants were performed using human islets or murine beta-cell-specific HIP-la-null (beta-HIP-1 alpha-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-l alpha. beta-HIF-1 alpha-null transplants had poor outcomes, demonstrating that lack of HIP-l alpha impaired transplant efficiency. Increasing HIP-la improved outcomes for mouse and human islets. No effect was seen in beta-HIF-l alpha-null islets. The mechanism was decreased apoptosis, resulting in increased beta-cell mass posttransplantation. These findings show that HIP-1 alpha is a protective factor and is required for successful islet transplant outcomes. Iron chelation with DFO markedly improved transplant success in a HIPl alpha-dependent manner, thus demonstrating the mechanism of action. DFO, approved for human use, may have a therapeutic role in the setting of human islet transplantation.
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