A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells

The putative induction of adult b-cell regeneration represents a promising approach for the treatment of type 1 diabetes. Toward this ultimate goal, it is essential to develop an inducible model mimicking the long-lasting disease progression. In the current study, we have established a novel b-cell ablation mouse model, in which the b-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the b-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IAD/D). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted b-cell death. In this model, we observed b-cell regeneration that resulted in a complete recovery of the b-cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining b-cells is the prominent mechanism acting to compensate for the massive b-cell loss in young but also aged mice. Interestingly, at any age, we also detected b-like cells expressing the glucagon hormone, suggesting a transition between a- and b-cell identities or vice versa. Taken together, the TIF-IAD/D mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting b-cell regeneration.