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

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

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)78-90.e4
JournalCell Stem Cell
Volume22
Issue number1
DOIs
StatePublished - Jan 4 2018

Bibliographical note

Funding Information:
The authors would like to acknowledge the generosity and support of Dr. Martin Jendrisak and the entire team of the Gift of Hope Organ & Tissue Donor Network in Chicago for providing the human pancreas tissues used in the present study. We thank Jay Kolls and William Horne from University of Pittsburgh Health Sciences Sequencing Core at Children's Hospital of Pittsburgh for RNA-seq analysis. X.X. was supported by a Tenure-track Assistant Professor startup from the Pediatric Division of Children's Hospital of Pittsburgh. G.K.G. was supported by the NIH (grants R01DK098196, R01DK111460, and R01DK112836), Juvenile Diabetes Research Foundation (1-INO-2014-167-A-V), and the Children's Hospital of Pittsburgh. P.W. and S.R. were supported by the University of Chicago DRTC Grant #P30 DK020595 and CRC- National Center for Advancing Transitional Sciences of the NIH Grant #UL1TR000430. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
The authors would like to acknowledge the generosity and support of Dr. Martin Jendrisak and the entire team of the Gift of Hope Organ & Tissue Donor Network in Chicago for providing the human pancreas tissues used in the present study. We thank Jay Kolls and William Horne from University of Pittsburgh Health Sciences Sequencing Core at Children’s Hospital of Pittsburgh for RNA-seq analysis. X.X. was supported by a Tenure-track Assistant Professor startup from the Pediatric Division of Children’s Hospital of Pittsburgh . G.K.G. was supported by the NIH (grants R01DK098196 , R01DK111460 , and R01DK112836 ), Juvenile Diabetes Research Foundation ( 1-INO-2014-167-A-V ), and the Children's Hospital of Pittsburgh . P.W. and S.R. were supported by the University of Chicago DRTC Grant # P30 DK020595 and CRC- National Center for Advancing Transitional Sciences of the NIH Grant # UL1TR000430 . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • MafA
  • NOD
  • Pdx1
  • adoptive transfer
  • alpha cells
  • beta cells
  • human islets
  • intraductal viral infusion
  • islet transplantation
  • lineage tracing

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