Insulin-Producing Beta-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.