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Cell Cycle. 2014;13(24):3948-57. doi: 10.4161/15384101.2014.952176.

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

Author information

1
a Max-Planck Institute for Biophysical Chemistry ; Department of Molecular Cell Biology ; RG Molecular Cell Differentiation ; Goettingen , Germany.

Abstract

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

KEYWORDS:

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

PMID:
25558832
PMCID:
PMC4614696
DOI:
10.4161/15384101.2014.952176
[Indexed for MEDLINE]
Free PMC Article

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