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

Risheng Ye, Miao Wang, Qiong A. Wang, Stephen B. Spurgin, Zhao V. Wang, Kai Sun, Philipp E. Scherer

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StateAccepted/In press - Apr 4 2016

Fingerprint

Regeneration
Tamoxifen
Pharmacology
Apoptosis
Acinar Cells
Doxycycline
Cell Lineage
Parity
Cell Differentiation
Pancreas
Obesity
Insulin
Diet

Keywords

  • Adult β-cell origins
  • Lineage tracing
  • Nkx6.1
  • Tamoxifen artifacts

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Autonomous interconversion between adult pancreatic α-cells and β-cells after differential metabolic challenges. / Ye, Risheng; Wang, Miao; Wang, Qiong A.; Spurgin, Stephen B.; Wang, Zhao V.; Sun, Kai; Scherer, Philipp E.

In: Molecular Metabolism, 04.04.2016.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Wang, Zhao V.

AU - Sun, Kai

AU - Scherer, Philipp E.

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