Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets.
OBJECTIVE
Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation.


METHODS
Pancreatic islets of TSP-1-deficient (TSP-1(-/-)) mice or wild-type islets transfected with siRNA for TSP-1 were transplanted beneath the renal capsule of syngeneic or immunocompromised recipient mice.


RESULTS
Both genetically TSP-1(-/-) islets and TSP-1 siRNA-transfected islet cells demonstrated an increased vascular density when compared with control islets 1 month after transplantation. This was also reflected in a markedly increased blood perfusion and oxygenation of the grafts. The functional importance of the improved vascular engraftment was analyzed by comparing glucose-stimulated insulin release from islet cells transfected with either TSP-1 siRNA or scramble siRNA before implantation. These experiments showed that the increased revascularization of grafts composed of TSP-1 siRNA-transfected islet cells correlated to increments in both their first and second phase of glucose-stimulated insulin secretion.


CONCLUSIONS
Our findings demonstrate that inhibition of TSP-1 in islets intended for transplantation may be a feasible strategy to improve islet graft revascularization and function.
Olerud
Johan
J
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Johansson
Magnus
M
Lawler
Jack
J
Welsh
Nils
N
Carlsson
Per-Ola
PO
D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D006085:Graft Survival / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000098:blood supply*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D014162:Transfection
D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D005947:Glucose