Identification of Signaling Pathways Regulating Beta Cell Regeneration in Zebrafish

Diabetes is becoming a leading health issue worldwide. It occurs under insulin resistance/deficiency and when insulin-producing pancreatic beta-cell mass is dramatically reduced. Besides therapeutic strategies to preserve beta-cell mass and function and improve insulin treatments, beta-cell replacement constitutes a promising alternative to replenish the pancreas with functional beta-cells. Beta-cell neogenesis can be achieved from different pancreatic cell types leading to the hope that triggering regeneration could be harnessed in future therapies. Still, mammals show limited regenerative capabilities, making difficult the study of these mechanisms. In contrast, zebrafish is extensively used for regeneration studies notably of beta-cells.
We recently showed that the adult zebrafish ducts display characteristics of embryonic pancreatic progenitors that give rise to beta-cells in physiological and induced diabetic condition*. To better understand the molecular mechanisms underlying this potential, genes and signaling pathways regulated in the zebrafish pancreatic ducts after beta-cell ablation have been identified by transcriptomic profiling. For functional studies, we have developed an assay using 7-20 days old larvae to investigate the role of selected candidate pathways in beta-cell regeneration with pharmacological inhibitors/activators and by transgenic overexpression of candidate signaling factors. These results should provide new hints to help improve regenerative competences in mammals.