Hypoxia-inducible factor-1α (HIF-1α) potentiates β-cell survival after islet transplantation of human and mouse islets.
A high proportion of β-cells die within days of islet transplantation. Reports suggest that induction of hypoxia-inducible factor-1α (HIF-1α) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-1α protects β-cells  during transplantation. Transplants were performed using human islets or murine β-cell-specific HIF-1α-null (β-HIF-1α-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-1α. β-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 β-HIF-1α-null islets. The mechanism was decreased apoptosis, resulting in increased β-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.
Diabetes and Transcription Factors Group, Garvan Institute of Medical Research GIMR, Sydney NSW 2010, Australia.
Rebecca A
RA
Stokes
Kim
K
Cheng
Natasha
N
Deters
Sue Mei
SM
Lau
Wayne J
WJ
Hawthorne
Philip J
PJ
O'Connell
Jessica
J
Stolp
Shane
S
Grey
Thomas
T
Loudovaris
Thomas W
TW
Kay
Helen E
HE
Thomas
Frank J
FJ
Gonzalez
Jenny E
JE
Gunton
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit