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Centroacinar Cells Are Progenitors That Contribute to Endocrine Pancreas Regeneration

View Article: PubMed Central - PubMed

ABSTRACT

Diabetes is associated with a paucity of insulin-producing β-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in β-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after β-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both β-cell neogenesis and β-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis.

No MeSH data available.


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β-Cell ablation and regeneration. A: ins:NTR transgene (see research design and methods). SST, somatostatin2. B and C: Three days following treatment, control transgenic fish (B) compared with MTZ-treated fish (C). Insulin-expressing β-cells (green) were nearly absent from islets. Anti-insulin (green), anti-glucagon (red), DAPI (blue). Scale bars = 50 μm. D: The percentage of β-cells per islet returns to control levels by MTZ +17 days. E: Blood glucose levels in MTZ- and vehicle-treated fish. β-Cell ablation results in hyperglycemia, which returns to control levels by MTZ +17 days. Ctrl, control; D, day; N, number of fish analyzed. *P < 0.05; ns, not significant, t test compared with control.
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Figure 4: β-Cell ablation and regeneration. A: ins:NTR transgene (see research design and methods). SST, somatostatin2. B and C: Three days following treatment, control transgenic fish (B) compared with MTZ-treated fish (C). Insulin-expressing β-cells (green) were nearly absent from islets. Anti-insulin (green), anti-glucagon (red), DAPI (blue). Scale bars = 50 μm. D: The percentage of β-cells per islet returns to control levels by MTZ +17 days. E: Blood glucose levels in MTZ- and vehicle-treated fish. β-Cell ablation results in hyperglycemia, which returns to control levels by MTZ +17 days. Ctrl, control; D, day; N, number of fish analyzed. *P < 0.05; ns, not significant, t test compared with control.

Mentions: Tg(HS4-sst2:CFP;ins:PhiYFP-m-dest1-2TA-nfsB)lmc009 (abbreviated ins:NTR) carries a transgene containing 1) insulin promoter driving a zebrafish codon–optimized NTR-T2A–yellow fluorescent protein (YFP) open-reading frame and 2) somatostatin2 promoter/enhancer driving CFP transcription (Fig. 4A). Other lines are listed in Supplementary Table 2.


Centroacinar Cells Are Progenitors That Contribute to Endocrine Pancreas Regeneration
β-Cell ablation and regeneration. A: ins:NTR transgene (see research design and methods). SST, somatostatin2. B and C: Three days following treatment, control transgenic fish (B) compared with MTZ-treated fish (C). Insulin-expressing β-cells (green) were nearly absent from islets. Anti-insulin (green), anti-glucagon (red), DAPI (blue). Scale bars = 50 μm. D: The percentage of β-cells per islet returns to control levels by MTZ +17 days. E: Blood glucose levels in MTZ- and vehicle-treated fish. β-Cell ablation results in hyperglycemia, which returns to control levels by MTZ +17 days. Ctrl, control; D, day; N, number of fish analyzed. *P < 0.05; ns, not significant, t test compared with control.
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Related In: Results  -  Collection

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Figure 4: β-Cell ablation and regeneration. A: ins:NTR transgene (see research design and methods). SST, somatostatin2. B and C: Three days following treatment, control transgenic fish (B) compared with MTZ-treated fish (C). Insulin-expressing β-cells (green) were nearly absent from islets. Anti-insulin (green), anti-glucagon (red), DAPI (blue). Scale bars = 50 μm. D: The percentage of β-cells per islet returns to control levels by MTZ +17 days. E: Blood glucose levels in MTZ- and vehicle-treated fish. β-Cell ablation results in hyperglycemia, which returns to control levels by MTZ +17 days. Ctrl, control; D, day; N, number of fish analyzed. *P < 0.05; ns, not significant, t test compared with control.
Mentions: Tg(HS4-sst2:CFP;ins:PhiYFP-m-dest1-2TA-nfsB)lmc009 (abbreviated ins:NTR) carries a transgene containing 1) insulin promoter driving a zebrafish codon–optimized NTR-T2A–yellow fluorescent protein (YFP) open-reading frame and 2) somatostatin2 promoter/enhancer driving CFP transcription (Fig. 4A). Other lines are listed in Supplementary Table 2.

View Article: PubMed Central - PubMed

ABSTRACT

Diabetes is associated with a paucity of insulin-producing &beta;-cells. With the goal of finding therapeutic routes to treat diabetes, we aim to find molecular and cellular mechanisms involved in &beta;-cell neogenesis and regeneration. To facilitate discovery of such mechanisms, we use a vertebrate organism where pancreatic cells readily regenerate. The larval zebrafish pancreas contains Notch-responsive progenitors that during development give rise to adult ductal, endocrine, and centroacinar cells (CACs). Adult CACs are also Notch responsive and are morphologically similar to their larval predecessors. To test our hypothesis that adult CACs are also progenitors, we took two complementary approaches: 1) We established the transcriptome for adult CACs. Using gene ontology, transgenic lines, and in situ hybridization, we found that the CAC transcriptome is enriched for progenitor markers. 2) Using lineage tracing, we demonstrated that CACs do form new endocrine cells after &beta;-cell ablation or partial pancreatectomy. We concluded that CACs and their larval predecessors are the same cell type and represent an opportune model to study both &beta;-cell neogenesis and &beta;-cell regeneration. Furthermore, we show that in cftr loss-of-function mutants, there is a deficiency of larval CACs, providing a possible explanation for pancreatic complications associated with cystic fibrosis.

No MeSH data available.


Related in: MedlinePlus