Diabetologia. 2016 Mar;59(3):522-32. doi: 10.1007/s00125-015-3838-7. Epub 2015 Dec 23.

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

Cavelti-Weder C¹, Li W^2,3, Zumsteg A³, Stemann-Andersen M¹, Zhang Y³, Yamada T¹, Wang M³, Lu J³, Jermendy A¹, Bee YM¹, Bonner-Weir S¹, Weir GC¹, Zhou Q⁴.

Abstract

AIMS/HYPOTHESIS:

Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined.

METHODS:

Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors.

RESULTS:

We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells.

CONCLUSIONS/INTERPRETATION:

Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.