title: A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells.
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.
authors.affiliation: a Max-Planck Institute for Biophysical Chemistry ; Department of Molecular Cell Biology ; RG Molecular Cell Differentiation ; Goettingen , Germany.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Shamsi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D054338:Cell Transdifferentiation; D004195:Disease Models, Animal; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D013629:Tamoxifen / Q000633:toxicity
chemical_list: D001786:Blood Glucose; D007328:Insulin; D035463:Pol1 Transcription Initiation Complex Proteins; C491074:Rrn3 protein, mouse; D013629:Tamoxifen
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