A high proportion of beta cells die within days of islet transplantation due to numerous factors limiting the effectiveness of these procedures for individuals with T1D. This may also have implications for the effectiveness of implanted encapsulated beta cell therapies. One important challenge to a successful transplant is sustaining sufficient oxygen levels around the transplanted beta cells to keep them alive. Studies have suggested that expression of certain factors is triggered by low oxygen levels and their expression predicts poor transplant outcomes as a measure of the stressed conditions around the transplanted cells. It is thought that the production of a factor called HIF-1a is a way that beta cells can compensate for the low local oxygen levels and protect themselves during transplantation. In this study, transplants were performed using human islets with or without the HIF-1a factor and with or without treatment with deferoxamine (DFO), a drug that can increase levels of HIF-1a. Transplants without the HIF-1a factor had poor outcomes, demonstrating that a lack of HIF-1a impaired transplant effectiveness. Increasing HIF-1a improved outcomes for mouse and human islets. The mechanism by which this factor works was to decrease beta cell death, resulting in increased beta cell numbers post-transplantation. These findings show that HIF-1a is a protective factor and is required for successful islet transplant outcomes. DFO, a drug approved for human use to remove excess iron from the body in anemic patients and other conditions, may have a therapeutic role in improving outcomes of human islet transplantation because of its ability to increase levels of HIF-1a.
Ramifications for Individuals with T1D:
Islet response to low oxygen levels is a concern for islet replacement therapies and is relevant to developing successful encapsulation technologies. This study identified a pathway that may be useful to promote beta cell survival by overcoming the less than ideal environment following a beta cell transplant.
This study was funded in part by JDRF.
Investigators and Institutions:
This study was conducted by Dr. Jenny Gunton and her colleagues at the St. Vincent Institute in Australia.
Stokes RA, Cheng K, and others. Hypoxia-inducible factor-1a (HIF-1a) potentiates beta-cell survival after islet transplantation of human and mouse islets. Cell Transplant. 2013;22(2):253-66. doi: 10.3727/096368912X647180. Epub 2012 Jun 15.