title: Cotransplantation of Polymerized Hemoglobin Reduces β-Cell Hypoxia and Improves β-Cell Function in Intramuscular Islet Grafts.
abstract: BACKGROUND
  Muscle is a promising alternative site for islet transplantation that facilitates rapid restoration of islet vascularization. However, the development of fibrosis suggests massive cellular death after transplantation. This study tested the hypothesis that islet graft function is limited by hypoxia-related death early after intramuscular transplantation, but that this can be overcome by cotransplantation of an oxygen carrier, that is, polymerized bovine hemoglobin (PolyHb).
  
  
  METHODS
  Two hundred islets were transplanted with or without different doses of PolyHb intramuscularly to nondiabetic C57BL/6 and diabetic C57BL/6 nu/nu mice. β-cell hypoxia and apoptosis were evaluated by immunohistochemistry after injection of the biochemical marker pimonidazole or by staining for caspase-3, respectively. Blood glucose concentrations were monitored for 30 days after islet transplantation and animals were then subjected to an intravenous glucose tolerance test.
  
  
  RESULTS
  Substantial hypoxia was observed in control islet grafts during the first 4 days after transplantation. Cotransplantation of PolyHb resulted in a dose-dependent reduction of β-cell hypoxia, but β-cell apoptosis was only reduced by cotransplantation of low-dose PolyHb (0.03 mg/g body weight) due to the inflammatory effects of higher PolyHb concentrations. Cotransplantation of low-dose PolyHb resulted in improved islet graft function 30 days after transplantation in diabetic mice, with a glucose tolerance comparable to transplantation of 50% more islets.
  
  
  CONCLUSIONS
  We conclude that cotransplantation of islets with PolyHb can be used to effectively bridge the critical hypoxic phase immediately after transplantation, improve islet graft function, and reduce the number of islets needed for successful intramuscular transplantation.
authors.affiliation: 1 Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. 2 Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 3 William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH.
authors.forename: Daniel
authors.initials: D
authors.lastname: Espes
authors.forename: Joey
authors.initials: J
authors.lastname: Lau
authors.forename: My
authors.initials: M
authors.lastname: Quach
authors.forename: Uddyalok
authors.initials: U
authors.lastname: Banerjee
authors.forename: Andre F
authors.initials: AF
authors.lastname: Palmer
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Carlsson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival; D005951:Glucose Tolerance Test; D006454:Hemoglobins / Q000737:chemistry*; D000860:Hypoxia / Q000473:pathology*; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009132:Muscles / Q000473:pathology*; D010100:Oxygen / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*
chemical_list: D001786:Blood Glucose; D006454:Hemoglobins; D007328:Insulin; D011108:Polymers; C080663:polymerized bovine hemoglobin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D010100:Oxygen