Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification

To investigate the role of the vasculature in pancreatic beta-cell regeneration, we crossed a zebrafish beta-cell ablation model into the avascular npas4l mutant (i.e. cloche). Surprisingly, beta-cell regeneration increased markedly in npas4l mutants owing to the ectopic differentiation of beta-cell in the mesenchyme, a phenotype not previously reported in any models. The ectopic beta-cell expressed endocrine markers of pancreatic beta-cell, and also responded to glucose with increased calcium influx. Through lineage tracing, we determined that the vast majority of these ectopic beta-cell has a mesodermal origin. Notably, ectopic beta-cell were found in npas4l mutants as well as following knockdown of the endothelial/myeloid determinant Etsrp. Together, these data indicate that under the perturbation of endothelial/myeloid specification, mesodermal cells possess a remarkable plasticity enabling them to form beta-cell, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for beta-cell regeneration.

Automated summary

Research showed that in the zebrafish model, beta-cell regeneration significantly increased in the avascular npas4l mutant, primarily due to ectopic differentiation of beta-cells in the mesenchyme. Through lineage tracing experiments, it was determined that the majority of ectopic beta-cells originated from the mesoderm, demonstrating remarkable cellular plasticity. These findings suggest that cells from different differentiation pathways can form beta-cells under certain conditions, potentially serving as an alternative source for beta-cell regeneration.