Pancreatic β-Cell Regeneration in TIF-IA Knockout Mice

by Farnaz Shamsi
Doctoral thesis
Date of Examination:2014-07-02
Date of issue:2014-09-30
Advisor:Prof. Dr. Ahmed Mansouri
Referee:Prof. Dr. Tomas Pieler
Referee:Prof. Dr. Reinhard Schuh
Referee:Prof. Dr. Anastassia Stoykova
Referee:Prof. Dr. Ernst A. Wimmer
Referee:Dr. Roland Dosch
Persistent Address: http://dx.doi.org/10.53846/goediss-4696

 

 

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Abstract

English

As the sole source of insulin production in body, pancreatic β-cells play an essential role in glucose homeostasis. Diabetes mellitus is a chronic disease characterized by loss, reduction, and/or malfunction of β-cell mass. The putative induction of adult β-cell regeneration repre- sents a promising approach for the treatment of type 1 diabetes. Towards 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 β-cell ablation mouse model, in which the β-cell mass progressively declines, as seen in type 1 diabetes. The model is based on the β-cell specific genetic ablation of the transcription initiation factor 1A, TIF-IA, essential for RNA Polymerase I activity (TIF-IA∆/∆). Using this approach, we induced a slow apoptotic response that eventually leads to a protracted β-cell death. In this model, we observed β-cell regenera- tion that resulted in a complete recovery of the β-cell mass and normoglycemia. In addition, we showed that adaptive proliferation of remaining β-cells is the prominent mechanism acting to compensate for the massive β-cell loss in young but also aged mice. Interestingly, at any age, we also detected β-like cells expressing the glucagon hormone, suggesting a transition between α and β-cell identities or vice versa. Taken together, the (TIF-IA∆/∆) mouse model can be used to investigate the potential therapeutic approaches for type 1 diabetes targeting β-cell regeneration. RNA-sequencing of (TIF-IA∆/∆) pancreas provided the possibilty to look at β-cell regeneration at the molecular level and dissect out the cellular pathways induced in pancreas upon β-cell ablation. These signaling pathways work together to mediate β-cell stress response, metabolic adaptations, and tissue homeostasis. Using these data, we have identified some novel regulators of β-cell regeneration.
Keywords: Pancreas; Beta-cell regeneration; Diabetes
 
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