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

Rebecca A. Stokes, Kim Cheng, Natasha Deters, Sue Mei Lau, Wayne J. Hawthorne, Philip J. O'Connell, Jessica Stolp, Shane Grey, Thomas Loudovaris, Thomas W. Kay, Helen E. Thomas, Frank J. Gonzalez, Jenny E. Gunton

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)259-266
Number of pages8
JournalCell transplantation
Volume22
Issue number2
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Deferoxamine (DFO)
  • Diabetes
  • Hypoxia
  • Hypoxia-inducible factor-1α (HIF-1α)
  • Islet transplantation
  • β-cell function

ASJC Scopus subject areas

  • Medicine(all)

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