Hypoxia-Inducible Factor-la (HIF-l alpha) Potentiates beta-Cell Survival After Islet Transplantation of Human and Mouse Islets

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.