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

eLife

Linn Rautio¹  Nicole Schmitner¹  Ka-Cheuk Liu¹  Olov Andersson¹  Didier YR Stainier²  Kenny Mattonet²  Alethia Villasenor²  Sven Reischauer³  Ryota L Matsuoka⁴  Maria Bertuzzi⁵  Niki Radros⁶ 

[1] Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden;Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Cardio-Pulmonary Institute, Frankfurt, Germany; Medical Clinic I, (Cardiology/Angiology) and Campus Kerckhoff, Justus-Liebig-University Giessen, Giessen, Germany;Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States;Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden;Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden;

关键词: differentiation;    beta-cell regeneration;    ectopic beta-cells;    cellular origin;    Zebrafish;   

DOI  :  10.7554/eLife.65758

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY