title: ptf1a+,ela3l-cells are developmentally maintained progenitors for exocrine regeneration following extreme loss of acinar cells in zebrafish larvae.
abstract: The exocrine pancreas displays a significant capacity for regeneration and renewal. In humans and mammalian model systems, the partial loss of exocrine tissue, such as after acute pancreatitis or partial pancreatectomy induces rapid recovery via expansion of surviving acinar cells. In mouse it was further found that an almost complete removal of acinar cells initiates regeneration from a currently not well-defined progenitor pool. Here, we used the zebrafish as an alternative model to study cellular mechanisms of exocrine regeneration following an almost complete removal of acinar cells. We introduced and validated two novel transgenic approaches for genetically encoded conditional cell ablation in the zebrafish, either by caspase-8-induced apoptosis or by rendering cells sensitive to diphtheria toxin. By using theela3lpromoter for exocrine-specific expression, we show that both approaches allowed cell-type-specific removal of >95% of acinar tissue in larval and adult zebrafish without causing any signs of unspecific side effects. We find that zebrafish larvae are able to recover from a virtually complete acinar tissue ablation within 2 weeks. Using short-term lineage-tracing experiments and EdU incorporation assays, we exclude duct-associated Notch-responsive cells as the source of regeneration. Rather, a rare population of slowly dividingela3l-negative cells expressingptf1aand CPA was identified as the origin of the newly forming exocrine cells. Cells are actively maintained, as revealed by a constant number of these cells at different larval stages and after repeated cell ablation. These cells establishela3lexpression about 4-6 days after ablation without signs of increased proliferation in between. With onset ofela3lexpression, cells initiate rapid proliferation, leading to fast expansion of theela3l-positive population. Finally, we show that this proliferation is blocked by overexpression of the Wnt-signaling antagonistdkk1bIn conclusion, we show a conserved requirement for Wnt signaling in exocrine tissue expansion and reveal a potential novel progenitor or stem cell population as a source for exocrine neogenesis after complete loss of acinar cells.
authors.affiliation: Institute for Molecular Biology, CMBI, University of Innsbruck, 6020 Innsbruck Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitner
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Institute for Molecular Biology, CMBI, University of Innsbruck, 6020 Innsbruck Austria dirk.meyer@uibk.ac.at.
authors.forename: Dirk
authors.identifier: 0000-0002-4020-4484
authors.initials: D
authors.lastname: Meyer
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000378:metabolism; D009928:Organ Specificity; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D010183:Pancreatic Ducts / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells; D014157:Transcription Factors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D029961:Zebrafish Proteins; C062602:transcription factor PTF1; D010196:Pancreatic Elastase; C000625218:ela3l protein, zebrafish
keywords: Ablation systems; Exocrine pancreas; Ptf1a; Regeneration; Wnt pathway; Zebrafish