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

• Published in: eLife 2021-08, Vol.10
• Main Authors: Liu, Ka-Cheuk, Villasenor, Alethia, Bertuzzi, Maria, Schmitner, Nicole, Radros, Niki, Rautio, Linn, Mattonet, Kenny, Matsuoka, Ryota L, Reischauer, Sven, Stainier, Didier YR, Andersson, Olov
• Format: Article
• Language: English
• Subjects: Ablation; Beta cells; beta-cell regeneration; Calcium influx; Cell culture; Cell differentiation; cellular origin; Developmental Biology; differentiation; ectopic beta-cells; Insulin; Medicin och hälsovetenskap; Mesenchyme; Mutants; Mutation; Pancreas; Phenotypes; Plasticity; Population; Siblings; Stem Cells and Regenerative Medicine
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.65758

To investigate the role of the vasculature in pancreatic β-cell regeneration, we crossed a zebrafish β-cell ablation model into the avascular npas4l mutant (i.e. cloche ). Surprisingly, β-cell regeneration increased markedly in npas4l mutants owing to the ectopic differentiation of β-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic β-cells expressed endocrine markers of pancreatic β-cells, and also responded to glucose with increased calcium influx. Through lineage tracing, we determined that the vast majority of these ectopic β-cells has a mesodermal origin. Notably, ectopic β-cells 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 β-cells, which are normally endodermal in origin. Understanding the restriction of this differentiation plasticity will help exploit an alternative source for β-cell regeneration.