Notch Signaling Is Required for Exocrine Regeneration After Acute Pancreatitis

Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University of Munich, München, Germany.
Gastroenterology (Impact Factor: 16.72). 03/2008; 134(2):544-55. DOI: 10.1053/j.gastro.2007.11.003
Source: PubMed


The mechanisms for tissue regeneration and renewal after acute pancreatitis are not well understood but may involve activation of Notch signaling. To study the effect of Notch signaling ablation during acute experimental pancreatitis, we used a chemical and genetic approach to ablate Notch signaling in cerulein-induced pancreatitis in mice.
Acute pancreatitis was induced by cerulein treatment in mice treated with the gamma-secretase inhibitor dibenzazepine or in conditional Notch1 knockout mice. Mice were characterized using immunohistologic, biochemical, and molecular methods. To investigate Notch and beta-catenin interaction, acinar 266-6 cells were analyzed using transfection and biochemical assays.
Loss of Notch signaling results in impaired regeneration after acute pancreatitis with fewer mature acinar cells in dibenzazepine-treated and Notch1-deficient mice in the regenerative phase 3 days after induction. beta-catenin expression was increased and prolonged during exocrine regeneration. Crosstalk between Notch and beta-catenin-mediated signaling was identified, with Notch1-IC inhibiting beta-catenin-mediated transcriptional activity. This inhibition was dependent on a functional RAM domain.
Inhibition of Notch signaling in vivo leads to impaired regeneration of the exocrine pancreas after acute pancreatitis. Our results suggest an interaction of Notch and Wnt signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells.

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    • "To determine if Dicer loss led to acinar stress associated with ADM, we examined expression of clusterin, a marker of stressed, de-differentiated acini[6], [25]. Clusterin was mainly absent in YFP+ acinar cells of control DicerHet; YFP and Kras; DicerHet; YFP mice, but was present in rare YFP+ ADM in Kras; DicerHet; YFP animals (Figure 2A, C). "
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    • "Following acute pancreatitis, acinar cells expressing oncogenic K-ras undergo a state of persistant dedifferentiation, ultimately leading to ADM and PanIN lesion formation [7]. Similarly, mice deficient for Notch1 in pancreatic epithelium also display impaired acinar regeneration following acute pancreatitis [9]. Therefore, activation of K-ras and deletion of Notch1 may cooperate to inhibit the regeneration process, resulting in a population of cells more susceptible to PanIN formation. "
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    • "To examine the role of EZH2 in tissue regeneration, we exploited an established experimental model of pancreatic epithelial injury and repair involving repetitive administration of supraphysiological levels of cerulein, a decapeptide analog of the pancreatic secretagogue cholecystokinin (Materials and Methods; Jensen et al. 2005; Fendrich et al. 2008; Siveke et al. 2008). Consistent with published observations, cerulein treatment induced severe exocrine pancreatic injury, which was readily observed within 1–3 d after the final administration and was histologically characterized by disordered acinar structure and abundant presence of metaplastic lesions (Fig. 1A). "
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