Decoding pancreatic endocrine cell differentiation and β cell regeneration in zebrafish

In contrast to mice, zebrafish have an exceptional yet elusive ability to replenish lost beta cells in adulthood. Understanding this framework would provide mechanistic insights for beta cell regeneration, which may be extrapolated to humans. Here, we characterize a krt4-expressing ductal cell type, which is distinct from the putative Notch-responsive cells, showing neogenic competence and giving rise to the majority of endocrine cells during postembryonic development. Furthermore, we demonstrate a marked ductal remodeling process featuring a Notch-responsive to krt4(+) luminal duct transformation during late development, indicating several origins of krt4(+) ductal cells displaying similar transcriptional patterns. Single-cell transcriptomics upon a series of time points during beta cell regeneration unveil a previously unrecognized dlb(+) transitional endocrine precursor cell, distinct regulons, and a differentiation trajectory involving cellular shuffling through differentiation and dedifferentiation dynamics. These results establish a model of zebrafish pancreatic endocrinogenesis and highlight key values of zebrafish for translational studies of beta cell regeneration.