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 β cells in adulthood. Understanding this framework would provide mechanistic insights for β 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 β 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 β cell regeneration.