Hypoxia-inducible factor-1α (HIF-1α) potentiates β-cell survival after islet transplantation of human and mouse islets

A high proportion of b-cells die within days of islet transplantation. Reports suggest that induction of hypoxiainducible factor-1α (HIF-1α) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-1α protects b-cells during transplantation. Transplants were performed using human islets or murine b-cell-specific HIF-1α-null (b-HIF-1α-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-1α. b-HIF-1α-null transplants had poor outcomes, demonstrating that lack of HIF-1α impaired transplant efficiency. Increasing HIF-1α improved outcomes for mouse and human islets. No effect was seen in b-HIF-1α-null islets. The mechanism was decreased apoptosis, resulting in increased b-cell mass posttransplantation. These findings show that HIF-1α is a protective factor and is required for successful islet transplant outcomes. Iron chelation with DFO markedly improved transplant success in a HIF- 1α-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.