Dynamic Production of Hypoxia-Inducible Factor-1α in Early Transplanted Islets

Abstract

More than half of transplanted b -cells undergo apoptotic cell death triggered by nonimmunological factors within a few days after transplantation. To investigate the dynamic hypoxic responses in early transplanted islets, syngeneic islets were transplanted under the kidney capsule of balb/c mice. Hypoxiainducible factor-1a (HIF-1a ) was strongly expressed at post-transplant day (POD) 1, increased on POD 3, and gradually diminished on POD 14. Insulin secretion decreased on POD 3 in association with a significant increase of HIF-1a -related b -cell death, which can be suppressed by short-term hyperbaric oxygen therapy. On POD 7, apoptosis was not further activated by continually produced HIF-1a . In contrast, improvement of nerve growth factor and duodenal homeobox factor-1 (PDx-1) production resulted in islet graft recovery and remodeling. In addition, significant activation of vascular endothelial growth factor in islet grafts on POD 7 correlated with development of massive newly formed microvessels, whose maturation is advanced on POD 14 with gradual diminution of HIF-1a . We conclude that (1) transplanted islets strongly express HIF-1a in association with b -cell death and decreased insulin production until adequate revascularization is established and (2) early suppression of HIF-1a results in less b -cell death thereby minimizing early graft failure.

Nerve growth factor is associated with islet graft failure following intraportal transplantation

“…6 A possible explanation for this problem is that many islets are destroyed immediately following transplantation, before a vascular network is reestablished. [7][8][9][10][11][12] Although native islets in the pancreas have a rich microvasculature, islet blood vessels are disrupted during islet isolation. Proper revascularization of the transplanted islets is of great importance for the function and survival of islet grafts.…”

“…Specimens were stained by immunohistochemistry for VEGF for vascularization 50,51 and HIF-1a to determine hypoxia. 11,12 Primary antibodies were goat anti-VEGF antibody (Santa Cruz Biotechnology Inc., sc-1836) diluted 1:50, and goat anti-HIF-1a antibody (Santa Cruz Biotechnology Inc., sc-12542) diluted 1:25. After incubating with biotinylated secondary Immunoglobulin G antibody (Vector Laboratories, PK-6105), a peroxidase substrate solution containing DAB (Brown for VEGF and HIF-1a) was used for visualization and counterstained with hematoxylin.…”

Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials

“…Providing sufficient oxygen delivery for implants containing highly metabolically active cells, such as those comprising pancreatic islets, is particularly challenging (8,9). Not only is the oxygen consumption rate for pancreatic islets elevated compared with many other cell types, they are also susceptible to functional impairment even at moderate oxygen tensions (9)(10)(11).…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…Hyperbaric oxygen therapy has been shown to mitigate hypoxic conditions during early post-islet transplantation in recipient animals frequently exposed to high pressure oxygen. This therapy improves functionality of islets transplanted intraportally or under the kidney capsule, reduces apoptosis, HIF-1a and VEGF expression, and enhances vessel maturation (132,136).…”