Improvement of beta cell function in intraportal transplantation of islet cell cluster using secretion signal peptide-linked exendin-4 gene

Abstract

One of the major obstacles to successful intraportal islet transplantation is the early portal vein embolization elicited by the infused islets. Thus, reducing the size and the number of islets is an important process to alleviate the damage of liver after intraportal islet transplantation. In our previous studies, we developed a strategy to construct genetically modified islet cell clusters (ICCs) and demonstrated their superiority in maintaining better viability and functionality in vivo. In this study, signal-peptide linked exendin-4 transduced islet cell clusters (Sp-Ex-4 ICCs) were used to reverse diabetes after intraportal islet transplantation in hyperglycemic mouse model. Group of mice receiving 500 islet equivalent (IEQ) of unmodified ICCs failed to restore normoglycemia following transplantation. Although 500 IEQ of ICCs was insufficient to reverse hyperglycemia in diabetic mice, no significant acute liver damage or life-threatening liver embolization was observed. When 1000 IEQ ICCs were infused into the portal vein, all animals died within 24 h post-surgery. In order to clarify the effect of Sp-Ex-4 gene transduction in improving ICCs functionality, 500 IEQ of Sp-Ex-4 ICCs were infused into the portal vein of diabetic mice. Following transplantation, 75% of diabetic mice returned to normoglycemia and the survival fraction was 100%. In conclusion, intraportal transplantation of Sp-Ex-4 ICCs successfully reversed diabetes in hyperglycemic mice by reducing the mass required for the treatment. Therefore, intraportal transplantation of small islets (genetically engineered ICCs) can be proposed as a new strategy to overcome early graft embolization after intraportal transplantation.