Pancreatic Beta Cell Regeneration: Duct Cells Act as Progenitors in Adult Zebrafish

Diabetes is characterized by the loss of insulin producing beta cells. Although different therapeutic strategies do exist, they lack precise and dynamic control of glycemia as carried out by endogenous beta cells. One promising alternative is to replenish the pancreas with bona fide functional beta cells by triggering regeneration mechanisms. Previous studies have shown beta cell neogenesis but still remain controversial about their origin as they used different models. However, among the different hypotheses, it is tempting to assume that pancreatic ducts contain progenitor/precursor cells in adults. The latter is supported by the fact that the embryonic duct epithelium gives rise to the endocrine lineage, and that in healthy and diabetic human adults, insulin positive cells could be found next to or in pancreatic ducts.
Despite these observations, mammals show very limited regenerative capabilities, making it difficult to investigate those mechanisms. In contrast, zebrafish are extensively used for regeneration studies. The ability of adult zebrafish to regenerate its beta cells and restore normoglycemia after massive beta cell ablation has already been shown. Our work focuses on the understanding of the underlying mechanisms leading to this retained potential. Here we show that adult pancreatic duct cells act as progenitors, giving rise to beta cells, in physiological and induced diabetic condition in vivo. To get insight into this process, we conducted RNA-seq experiments on zebrafish pancreatic duct cells. By this mean we could identify new ductal markers and noticed that adult duct cells also show strong expression of embryonic pancreatic progenitor markers. In our ongoing comparative analyses we are deciphering the key genes and pathways needed to set in motion the regenerative machinery. The differences between zebrafish and mammal duct cells that will thereby be underlined might then be transposed to mammalian model s to restore regenerative processes.