Peripheral mobilization of recipient bone marrow-derived endothelial progenitor cells enhances pancreatic islet revascularization and engraftment after intraportal transplantation

Abstract

Background: Pancreatic islet transplantation has been validated as a treatment for type 1 diabetes. However, a high number of islets is required to establish euglycemia. Transplantation of islets leads to loss of islet vasculature, which requires revascularization to ensure adequate survival. Islet vascular density in transplanted islets is markedly decreased compared with endogenous islets. The feasibility of revascularization of ischemic tissues by mobilizing endothelial progenitor cells or angioblasts has been demonstrated. Therefore, we investigated the therapeutic potential of angioblast mobilization for stimulation of islet revascularization and therefore engraftment after transplantation.

Methods: FVB/NJ mice underwent bone marrow transplantation from transgenic mice constitutively expressing beta-galactosidase encoded by LacZ under regulation of the endothelial cell-specific promoter TIE-2 (FEV/NJ-TIE-2-LacZ). Three weeks after reconstitution, animals received an intrahepatic islet syngeneic infusion (FVB/NJ donors). The contribution of angioblasts into sites of islet revascularization was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), beta-galactosidase (beta-gal) activity, and immunohistochemistry. Islet vascular density was assessed morphometrically followed by in situ BS-1 lectin staining and functional islet mass after transplantation by metabolic studies. Angioblasts were mobilized with murine granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.5 microg/day/7 days).

Results: An islet dose-dependent increase in beta-gal was demonstrated after transplantation. These results were confirmed by RT-PCR and immunohistochemistry. GM-CSF increased the number of peripheral angioblasts and their localization into sites of islet revascularization. A significant increase in islet vascular density was observed in animals treated with GM-CSF versus controls. Higher functional islet mass was demonstrated in animals treated with GM-CSF.

Conclusions: Augmentation of angioblasts in the peripheral circulation resulted in higher islet vascular density and engraftment. This novel strategy may improve the results in clinical islet transplantation.