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

作者：Shamsi Farnaz; Parlato Rosanna; Collombat Patrick; Mansouri Ahmed^*

来源：Cell Cycle, 2014, 13(24): 3948-3957.

DOI：10.4161/15384101.2014.952176

• -cell proliferation
• diabetes
• insulin
• islet of Langerhans
• pancreatic -cell
• regeneration
• TIF-IA
• TIF-IA
• Transcription Initiation Factor 1A
• RIP
• Rat Insulin Promoter
• Pdx1
• Pancreatic and duodenal homeobox 1
• Ngn3
• Neurogenin 3
• Pax4
• Paired box gene 4
• rDNA
• ribosomal DNA

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

• 出版日期2014-12-15