Regenerating insulin-producing β-cells ectopically from a mesodermal origin in the absence of endothelial specification

Abstract

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}-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic {beta}-cells expressed endocrine markers of pancreatic {beta}-cells, and also reduced glucose levels in the {beta}-cell ablation model. Through lineage tracing, we determined that the vast majority of these ectopic {beta}-cells derived from the mesodermal lineage. Notably, ectopic {beta}-cells were found in npas4l mutants as well as following knockdown of the endothelial determinant Etv2. Together, these data indicate that in the absence of endothelial specification, mesodermal cells possess a remarkable plasticity enabling them to form {beta}-cells, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for {beta}-cell regeneration.