Key Developmental Regulators Suggest Multiple Origins of Pancreatic Beta Cell Regeneration

Extensive efforts have been done to try to restore the lost beta cell mass for the cure of diabetes. Animal models have been established to provide evidences of cellular origins and contextual regulators of beta cell regeneration. Here, we used a zebrafish beta cell ablation and regeneration model to investigate beta cell neogenesis in the first few days after a near-total beta cell loss. Regeneration of beta cells first occurred within 7 h post-treatment. Developmental regulators such as neurod, pdx1, mnx1, and nkx2.2a were active in the regenerating beta cells, while at the same time suggesting different subpopulations of regenerative cellular origins. Using Cre/loxP-based lineage tracing, we showed that intrapancreatic ductal cells resisted to give rise to regenerating beta cells. Given that transdifferentiation of alpha cell and delta cell can regenerate beta cell, here we have provided further molecular evidence highly suggesting that the regenerating beta cells originate from multiple cellular origins.