Leveraging zebrafish to investigate pancreatic development, regeneration, and diabetes.

Based on recent single-cell transcriptomics and lineage tracing, sst1.1 + cell transdifferentiation and krt4 + cell differentiation have recently been recognized as the major sources of regeneration of insulin-producing cells in zebrafish. Large-scale in vivo small molecule screening has been successfully applied in zebrafish for the unbiased identification of chemicals promoting β-cell regeneration and glucose control. Multiple compounds have been validated to also promote β-cell proliferation, differentiation, or function in mammalian systems. Live imaging in zebrafish enables visualization of complex biological processes at the single-cell resolution in vivo (e.g., calcium flux in β-cells) as well as innervation and immune cell behaviors in the islet. Role of genes identified in human genetic data [e.g. genome-wide association studies (GWAS) and single-cell sequencing data] can be efficiently elucidated in zebrafish. The zebrafish has become an outstanding model for studying organ development and tissue regeneration, which is prominently leveraged for studies of pancreatic development, insulin-producing β-cells, and diabetes. Although studied for more than two decades, many aspects remain elusive and it has only recently been possible to investigate these due to technical advances in transcriptomics, chemical-genetics, genome editing, drug screening, and in vivo imaging. Here, we review recent findings on zebrafish pancreas development, β-cell regeneration, and how zebrafish can be used to provide novel insights into gene functions, disease mechanisms, and therapeutic targets in diabetes, inspiring further use of zebrafish for the development of novel therapies for diabetes. [ABSTRACT FROM AUTHOR]