A δ-cell subpopulation with a pro-β-cell identity contributes to efficient age-independent recovery in a zebrafish model of diabetes
Claudio Andrés Carril Pardo,
Laura Massoz,
Marie A Dupont,
David Bergemann,
Jordane Bourdouxhe,
Arnaud Lavergne,
Estefania Tarifeño-Saldivia,
Christian SM Helker,
Didier YR Stainier,
Bernard Peers,
Marianne M Voz,
Isabelle Manfroid
Affiliations
Claudio Andrés Carril Pardo
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium
Laura Massoz
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium
Marie A Dupont
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium
David Bergemann
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium
Jordane Bourdouxhe
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium
Arnaud Lavergne
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium; GIGA-Genomics core facility, University of Liège, Liège, Belgium
Estefania Tarifeño-Saldivia
Zebrafish Development and Disease Models laboratory, GIGA-Stem Cells, University of Liège, Liège, Belgium; Gene Expression and Regulation Laboratory, Department of Biochemistry and Molecular Biology, University of Concepción, Concepción, Chile
Christian SM Helker
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new Insulin-expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new insulin cells differ from the original β-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia. Their formation in response to β-cell destruction is fast, efficient, and age-independent. Bihormonal cells are transcriptionally close to a subset of δ-cells that we identified in control islets and that are characterized by the expression of somatostatin 1.1 (sst1.1) and by genes essential for glucose-induced Insulin secretion in β-cells such as pdx1, slc2a2 and gck. We observed in vivo the conversion of monohormonal sst1.1-expressing cells to sst1.1+ ins + bihormonal cells following β-cell destruction. Our findings support the conclusion that sst1.1 δ-cells possess a pro-β identity enabling them to contribute to the neogenesis of Insulin-producing cells during regeneration. This work unveils that abundant and functional bihormonal cells benefit to diabetes recovery in zebrafish.
