title: Autonomous interconversion between adult pancreatic α-cells and β-cells after differential metabolic challenges.
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.
  
  
  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.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Risheng
authors.initials: R
authors.lastname: Ye
authors.affiliation: Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Qiong A
authors.initials: QA
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Spurgin
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: philipp.scherer@utsouthwestern.edu.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
keywords: Adult β-cell origins; Lineage tracing; Nkx6.1; Tamoxifen artifacts