Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration

Autor: Bernard Peers, Aurélie Ghaye, Estefanía Tarifeño-Saldivia, Marianne Voz, Isabelle Manfroid, Virginie Von Berg, David Bergemann, Lydie Flasse
Jazyk: angličtina
Předmět:
Physiology
Cellular differentiation
Plant Science
duct
Structural Biology
Insulin-Secreting Cells
pancreas
multipotent progenitors
Zebrafish
Wnt Signaling Pathway
Genetics
nkx6.1
Receptors
Notch
centroacinar cells
diabetes
Agricultural and Biological Sciences(all)
Gene Expression Regulation
Developmental
Cell Differentiation
Cell biology
medicine.anatomical_structure
embryonic structures
PDX1
Stem cell
General Agricultural and Biological Sciences
Pancreas
Biotechnology
Research Article
Notch
animal structures
Ductal cells
Biology
General Biochemistry
Genetics and Molecular Biology
Wnt
lineage tracing
stem cells
medicine
Animals
Regeneration
Progenitor cell
Ecology
Evolution
Behavior and Systematics
Biochemistry
Genetics and Molecular Biology(all)
Multipotent Stem Cells
Cell Biology
Zebrafish Proteins
biology.organism_classification
beta cells
Multipotent Stem Cell
ascl1
Developmental Biology
Transcription Factors
Zdroj: BMC Biology
ISSN: 1741-7007
DOI: 10.1186/s12915-015-0179-4
Popis: Background In contrast to mammals, the zebrafish has the remarkable capacity to regenerate its pancreatic beta cells very efficiently. Understanding the mechanisms of regeneration in the zebrafish and the differences with mammals will be fundamental to discovering molecules able to stimulate the regeneration process in mammals. To identify the pancreatic cells able to give rise to new beta cells in the zebrafish, we generated new transgenic lines allowing the tracing of multipotent pancreatic progenitors and endocrine precursors. Results Using novel bacterial artificial chromosome transgenic nkx6.1 and ascl1b reporter lines, we established that nkx6.1-positive cells give rise to all the pancreatic cell types and ascl1b-positive cells give rise to all the endocrine cell types in the zebrafish embryo. These two genes are initially co-expressed in the pancreatic primordium and their domains segregate, not as a result of mutual repression, but through the opposite effects of Notch signaling, maintaining nkx6.1 expression while repressing ascl1b in progenitors. In the adult zebrafish, nkx6.1 expression persists exclusively in the ductal tree at the tip of which its expression coincides with Notch active signaling in centroacinar/terminal end duct cells. Tracing these cells reveals that they are able to differentiate into other ductal cells and into insulin-expressing cells in normal (non-diabetic) animals. This capacity of ductal cells to generate endocrine cells is supported by the detection of ascl1b in the nkx6.1:GFP ductal cell transcriptome. This transcriptome also reveals, besides actors of the Notch and Wnt pathways, several novel markers such as id2a. Finally, we show that beta cell ablation in the adult zebrafish triggers proliferation of ductal cells and their differentiation into insulin-expressing cells. Conclusions We have shown that, in the zebrafish embryo, nkx6.1+ cells are bona fide multipotent pancreatic progenitors, while ascl1b+ cells represent committed endocrine precursors. In contrast to the mouse, pancreatic progenitor markers nkx6.1 and pdx1 continue to be expressed in adult ductal cells, a subset of which we show are still able to proliferate and undergo ductal and endocrine differentiation, providing robust evidence of the existence of pancreatic progenitor/stem cells in the adult zebrafish. Our findings support the hypothesis that nkx6.1+ pancreatic progenitors contribute to beta cell regeneration. Further characterization of these cells will open up new perspectives for anti-diabetic therapies. Electronic supplementary material The online version of this article (doi:10.1186/s12915-015-0179-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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