Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

Publication date: 4 January 2018
Source:Cell Stem Cell, Volume 22, Issue 1
Author(s): Xiangwei Xiao, Ping Guo, Chiyo Shiota, Ting Zhang, Gina M. Coudriet, Shane Fischbach, Krishna Prasadan, Joseph Fusco, Sabarinathan Ramachandran, Piotr Witkowski, Jon D. Piganelli, George K. Gittes
Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin⁺ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

Graphical abstract

Teaser

Reprograming of endogenous mouse alpha cells into functional beta cells, which significantly delays diabetes onset in autoimmune diabetic mice, and the successful reprograming of human alpha cells into beta cells with the same strategy represent a promising way for treating type 1 diabetes.


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