IMPROVED VASCULAR ENGRAFTMENT AND GRAFT FUNCTION FOLLOWING INHIBITION OF THE ANGIOSTATIC FACTOR THROMBOSPONDIN-1 IN MOUSE PANCREATIC ISLETS

Abstract

Objective: Insufficient development of a new intra-islet capillary network following 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.

Research Design and 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 to control islets one month following 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 prior to 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.