TY - JOUR
T1 - A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells
AU - Shamsi, Farnaz
AU - Parlato, Rosanna
AU - Collombat, Patrick
AU - Mansouri, Ahmed
N1 - Funding Information:
This work was supported by the Max-Planck Society, the Juvenile Diabetes Research foundation (17-2011-16, 2-2010-567, 26-2008-639, 17-2013-426), the INSERM AVENIR program, the INSERM, the European Research Council (StG-2011-281265) the FMR (DRC20091217179), the ANR/BMBF (2009 GENO 105 01/01KU0906), the ‘‘Investments for the Future’’ LABEX SIGNALIFE (ANR-11-LABX-0028-01), Club Isatis, Mr and Mrs Dorato, the Fondation Générale de Santé, and the Foundation Schlumberger pour l’Education et la Recherche.
Publisher Copyright:
© 2014 Taylor & Francis Group, LLC.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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.
AB - 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.
KW - B-cell proliferation
KW - Diabetes
KW - Insulin
KW - Islet of langerhans
KW - Pancreatic b-cell
KW - Regeneration
KW - TIF-IA
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U2 - 10.4161/15384101.2014.952176
DO - 10.4161/15384101.2014.952176
M3 - Article
C2 - 25558832
AN - SCOPUS:84920587282
VL - 13
SP - 3948
EP - 3957
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 24
ER -