Characterization of the regenerated Insulin-producing cells following pancreatic β-cell destruction in zebrafish

Abstract

Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new Insulin-expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new insulin cells differ from the original β- cells as they are Somatostatin+ Insulin+, but are nevertheless functional and normalize glycemia. These bi-hormonal cells are transcriptionally close to a subset of δ-cells in normal islets characterized by the expression of somatostatin 1.1 (sst1.1), the β-cell genes pdx1, slc2a2 and gck, and the machinery for glucoseinduced Insulin secretion. β-cell destruction triggers massive sst1.1 δ-cell conversion to bihormonal cells. Our work shows that their pro- β-cell identity predisposes this zebrafish δ-cell subpopulation to efficient age-independent neogenesis of Insulinproducing cells and provides clues to restoring functional β-cells in mammalian diabetes models.