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Autonomous interconversion between adult pancreatic α-cells and β-cells after differential metabolic challenges

BACKGROUND: Evidence hints at the ability of β-cells to emerge from non-β-cells upon genetic or pharmacological interventions. However, their quantitative contributions to the process of autonomous β-cell regeneration without genetic or pharmacological manipulations remain to be determined. METHODS...

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Detalles Bibliográficos
Autores principales: Ye, Risheng, Wang, Miao, Wang, Qiong A., Spurgin, Stephen B., Wang, Zhao V., Sun, Kai, Scherer, Philipp E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921793/
https://www.ncbi.nlm.nih.gov/pubmed/27408770
http://dx.doi.org/10.1016/j.molmet.2016.05.001
Descripción
Sumario:BACKGROUND: Evidence hints at the ability of β-cells to emerge from non-β-cells upon genetic or pharmacological interventions. However, their quantitative contributions to the process of autonomous β-cell regeneration without genetic or pharmacological manipulations remain to be determined. METHODS & RESULTS: Using PANIC-ATTAC mice, a model of titratable, acute β-cell apoptosis capable of autonomous, and effective islet mass regeneration, we demonstrate that an extended washout of residual tamoxifen activity is crucial for β-cell lineage tracing studies using the tamoxifen-inducible Cre/loxP systems. We further establish a doxycycline-inducible system to label different cell types in the mouse pancreas and pursued a highly quantitative assessment to trace adult β-cells after various metabolic challenges. Beyond proliferation of pre-existing β-cells, non-β-cells contribute significantly to the post-challenge regenerated β-cell pool. α-cell trans-differentiation is the predominant mechanism upon post-apoptosis regeneration and multiparity. No contributions from exocrine acinar cells were observed. During diet-induced obesity, about 25% of α-cells arise de novo from β-cells. Ectopic expression of Nkx6.1 promotes α-to-β conversion and insulin production. CONCLUSIONS: We identify the origins and fates of adult β-cells upon post-challenge upon autonomous regeneration of islet mass and establish the quantitative contributions of the different cell types using a lineage tracing system with high temporal resolution.