Abstract
Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the ectopic expression of a single gene, Pax4. Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the Arx gene in α-cells is sufficient to promote the conversion of adult α-cells into β-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon(+) cells thereby generated being subsequently converted into β-like cells upon Arx inhibition. Of interest, through the generation and analysis of Arx and Pax4 conditional double-mutants, we provide evidence that Pax4 is dispensable for these regeneration processes, indicating that Arx represents the main trigger of α-cell-mediated β-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation*
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Diabetes Mellitus, Type 1 / genetics*
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 1 / therapy
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Disease Models, Animal
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Gene Expression Regulation
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Glucagon / genetics
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Glucagon / metabolism
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Glucagon-Secreting Cells / metabolism
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Glucagon-Secreting Cells / pathology
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics*
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Humans
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / metabolism*
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Islets of Langerhans / metabolism
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Islets of Langerhans / pathology
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Mice, Transgenic
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Paired Box Transcription Factors / genetics
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
Substances
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ARX protein, mouse
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Homeodomain Proteins
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Paired Box Transcription Factors
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Pax4 protein, mouse
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Transcription Factors
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Glucagon
Grants and funding
This work was supported by 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), the Max-Planck Society, Club Isatis, Mr and Mrs Dorato, the Fondation Générale de Santé, the Foundation Schlumberger pour l'Education et la Recherche, the DON Foundation (
www.sdon.nl), and the Fund for Scientific Research-Flanders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.