Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet‐transplantation enhances immediate post‐transplant islet graft function but not long‐term normoglycemia

Abstract

The liver as transplantation site for pancreatic islets is associated with significant loss of islets, which can be prevented by grafting in a prevascularized, subcutaneous scaffold. Supporting vascularization of a scaffold to limit the period of ischemia is challenging and was developed here by applying liposomes for controlled release of angiogenic factors. The angiogenic capacity of platelet‐derived growth factor, vascular endothelial growth factor, acidic fibroblast growth factor (aFGF), and basic FGF were compared in a tube formation assay. Furthermore, the release kinetics of different liposome compositions were tested. aFGF and L‐α‐phosphatidylcholine/cholesterol liposomes were selected to support vascularization. Two dosages of aFGF‐liposomes (0.5 and 1.0 μg aFGF per injection) were administered weekly for a month after which islets were transplanted. We observed enhanced efficacy in the immediate post‐transplant period compared to the untreated scaffolds. However, on the long‐term, glucose levels of the aFGF treated animals started to increase to diabetic levels. These results suggest that injections with aFGF liposomes do improve vascularization and the immediate restoration of blood glucose levels but does not facilitate the long‐term survival of islets. Our data emphasize the need for long‐term studies to evaluate potential beneficial and adverse effects of vascularization protocols of scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2533–2542, 2017.

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

“…This was the main rational to test the impact of SCFAs on β-cells [29,30]. In addition, we tested how SCFAs can reduce oxidative and nitrosative stress in human islets and β-cells after exposure to STZ [31]. We demonstrate the strong viability promoting effects and protection against oxidative and nitrosative stress by both acetate and butyrate at lower concentrations of 1 mM, while higher concentrations had adverse effects.…”

In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo

“…It has been suggested that stimulation of angiogenesis is critical to successful subcutaneous islet transplantation (47,51,55,68), prompting investigation of a number of vascularization strategies. Specifically, vascularization using empty devices or other synthetic materials pretransplantation of islets (16,35,45,46,61,62), oxygen generators (37,38), and cotransplantation of soluble factors (e.g., fibroblast growth factor, hepatocyte growth factor, and vascular endothelial growth factor) (29, 71) or cells (e.g., fibroblasts, mesenchymal stem cells, and endothelial cells) (48,49,71) have all been explored with variable success. For most of these strategies, there is a 1-to 4-wk posttransplantation delay for animals to achieve normoglycemia as islet health and site vascularization and mass transport properties presumably become sufficient for normal glucose homeostasis.…”

Extracellular matrix molecules and their potential contribution to the function of transplanted pancreatic islets

“…In recent studies, we have applied fibrin in polymeric scaffolds that serve as an artificial transplantation site for pancreatic islets under the skin [ 86 ]. This resulted in enhanced vascularisation and engraftment of islets, reducing the number of islets needed to achieve normoglycaemia in mice [ 86 , 87 ]. This might be explained by specific interactions of fibrin with some integrins in islets, including α v β 1 , which is known to be important for the function of transplanted islets [ 88 ].…”

“…Fibrin can also upregulate α v β 3 integrin expression, which prevents beta cell apoptosis [ 80 , 83 ]. Thus, fibrin is an excellent candidate for exogenous addition to islet grafts to enhance their survival [ 86 , 87 ].…”