Regenerating insulin-producing β-cells ectopically from a mesodermal origin in the absence of endothelial specification
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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.
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Joint Public Review:
The manuscript by Liu and colleagues is a very elegant study demonstrating the emergence of ectopic beta cells after beta cell specific ablation in zebrafish pancreas in a context in which vascularization of the larvae was altered in either npas4l mutants or etv2 morphants. Provocatively, the authors demonstrate the mesodermal origin of ectopic and functional beta cells using 2 mesodermal mapping strategies. This study is very well conducted with appropriate controls and rigorous statistical analyses. This study will likely impact the field of pancreas regeneration providing a novel source for beta cells within the adjacent mesodermal tissue.
This is an elegant study demonstrating the emergence of mesoderm-derived beta-like cells following beta-cell ablation in an endothelial cell deficient context. These findings will be of interest to scientists in the areas of regeneration and reprogramming, as they reveal a previously unknown degree of germ layer plasticity in the embryo. In the long term the study has potential impact in the diabetes field, as it reveals a novel path for redirecting somatic cells into insulin-producing cells in an in vivo context.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)