PT - JOURNAL ARTICLE AU - Liu, Ka-Cheuk AU - Villasenor, Alethia AU - Schmitner, Nicole AU - Radros, Niki AU - Rautio, Linn AU - Reischauer, Sven AU - Stainier, Didier Y.R. AU - Andersson, Olov TI - Regenerating insulin-producing β-cells ectopically from a mesodermal origin in the absence of endothelial specification AID - 10.1101/2021.02.01.429189 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.02.01.429189 4099 - http://biorxiv.org/content/early/2021/02/02/2021.02.01.429189.short 4100 - http://biorxiv.org/content/early/2021/02/02/2021.02.01.429189.full AB - 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 reduced glucose levels in the β-cell ablation model. Through lineage tracing, we determined that the vast majority of these ectopic β-cells derived from the mesodermal lineage. Notably, ectopic β-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 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.