Improvement of Beta Cell Function in Intraportal Transplantation of Islet Cell Cluster Using Secretion Signal Peptide-Linked Exendin-4 Gene = Improvement of Beta Cell Function in Intraportal Transplantation of Islet Cell Cluster Using Secretion Signal Peptide-Linked Exendin-4 Gene

다국어 초록 (Multilingual Abstract)

One of the major obstacles to successful intraportal islet transplantation is the early portal vein embolizationelicited by the infused islets. Thus, reducing the size and the number of islets is an important process to alleviatethe damage of liver after intraportal islet transplantation. In our previous studies, we developed a strategy to constructgenetically modified islet cell clusters (ICCs) and demonstrated their superiority in maintaining better viabilityand 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 micereceiving 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 liverdamage 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 improvingICCs 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, intraportaltransplantation of Sp-Ex-4 ICCs successfully reversed diabetes in hyperglycemic mice by reducing the mass requiredfor the treatment. Therefore, intraportal transplantation of small islets (genetically engineered ICCs) can be proposedas a new strategy to overcome early graft embolization after intraportal transplantation.