Obese individuals exhibit an increase in pancreatic β-cell mass, which is thought to be mediated through effects on β-cell proliferations since a nutrient sensitive β-cell progenitor population in the pancreas has not been identified. We have used a novel constitutive β-cell ablation model to show that β-cell loss and nutrient intake synergize to activate endogenous progenitors within the intrapancreatic ducts. Activation of ductal cells stimulates their proliferation and differentiation to endocrine fates. This process is associated with down- regulation of Notch signaling and activation of the nutrient sensor mTOR, revealing a nutrient sensitive progenitor population in the mature pancreas. We are now exploiting metabolic signals to bias the directed transdifferentiation of pancreatic cells to the endocrine fate. We have previously reported that inhibition of Ptf1a activity in acinar cells induces partial dedifferentiation accompanied by increased cell fate plasticity. As with endogenous progenitors, we find that mTOR signaling is required for acinar to endocrine transdifferentiation. We suggest that the temporal manipulation of metabolic signals will be essential for harnessing the potential of in vivo transdifferentiation strategies.
Funding support: JDRF and Diabetes Australia.