Identification of a direct progenitor population for differentiation to insulin-producing cells
The deficiency of functional insulin-producing cells is a common feature of type 1 and late-stage type 2 diabetes. Previous studies have suggested that mammals have very limited capacity for regeneration of insulin-producing cells, but researchers at Karolinska Institutet have found how zebrafish can form new cells and thereby provide clues to possible future possibilities in diabetes. The study is published in the scientific journal Science Advances.
In contrast to mammals, zebrafish possess an exceptional yet elusive ability to replenish lost insulin-producing cells in adulthood. Understanding this framework would provide mechanistic insights for regeneration of insulin-producing cells, which may be extrapolated to human.
"In this research project, we identify a pancreatic progenitor cell type, which gives rise to the majority of endocrine cells during development and growth of zebrafish" says Jiarui Mi from the Department of Cell and Molecular Biology Karolinska Institutet and the study's first author.
Reveals novel model for endocrinogenesis
These results establish a new model for generation of pancreatic endocrine cells in zebrafish, defining the main origin of new insulin-producing cells as a krt4-expressing ductal cell type. This model involves a remodeling process, in which scattered ductal cells first come together and form a luminal structure before gaining plasticity and ability to differentiate to endocrine cells. Moreover, this study highlights key values of zebrafish for translational studies of regeneration of insulin-producing cells, as it shows that endocrinogenesis is largely conserved when comparing adult zebrafish with embryonic mouse and human, as well as uncover previously unknown key molecular events governing formation and regeneration of insulin-producing cells.
"First we developed new transgenic zebrafish by knocking in genes used for tracing certain cellular lineages, i.e. to follow the specific cell type and its differentiated descendants. Then through combining the lineage-tracing strategy with single-cell transcriptomics we could enrich for the cells of interest and determine cellular events that precede the formation of mature insulin-producing cells. By studying a series of timepoints during regeneration of insulin-producing cells we uncover a previously unrecognized transitional endocrine precursor cell and a differentiation trajectory involving cellular shuffling through differentiation and de-differentiation dynamics. The in silico analyzes of single-cell transcriptomics were confirmed by histological and experimental follow-up studies." says Olov Andersson, the study's senior author.
Going forward Olov Andersson's lab are screening for small-molecule inducers of new insulin-producing cells derived from the cellular origin described in the current study. In doing so they hope to identify specific signaling pathways or molecular mechanisms that can increase the insulin-producing cell mass, perhaps including drugs that may be repurposed for this aim.
This work was supported by funding from The European Research Council, the Swedish Research Council, the Novo Nordisk Foundation, and Strategic Research Programmes at the Karolinska Institutet (SRP Diabetes and StratRegen).
Decoding pancreatic endocrine cell differentiation and β cell regeneration in zebrafish.
Mi J, Liu KC, Andersson O
Sci Adv 2023 Aug;9(33):eadf5142