d-cell conversion to insulin+ bihormonal cells in zebrafish

Restoring damaged b-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 b-cells arising following destruction. We show that most new insulin cells differ from the original b-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to b-cell destruction is fast, efficient and age-independent. Bihormonal cells are transcriptionally close to a subset of d-cells that we identified in control islets and which are characterized by the expression of somatostatin 1.1 (sst1.1) and by genes essential for glucose-induced Insulin secretion in ß-cells such as pdx1, slc2a2 and gck. We observed in vivo the conversion of monohormonal sst1.1-expressing cells to sst1.1+ ins+ bihormonal cells following b-cell destruction. Our findings support the conclusion that sst1.1 d-cells possess a pro-b identity enabling them to contribute to the neogenesis of Insulin-producing cells during regeneration. This work unveils that abundant and functional bihormonal cells benefit to diabetes recovery in zebrafish. Overall design: RNA-sequencing of 19 samples from adult fish 6–10 months old. d-cells (sst1.1:GFP +), ß-cells (ins:mCherry +) and Bi hormonal cells (sst1.1:GFP/ins:mCherry +). Transcriptomic profiles of 20 dpt (days post-treatment) control zebrafish sst1.1:GFP high and low 3 replicates for each one. And ins:mCherry + 7 replicates. Regenerated zebrafish sst1.1:GFP/ins:mCherry + bi-hormonal cells 6 replicates were generated