Notch signaling is required for exocrine regeneration after acute pancreatitis
Notch signaling is required for exocrine regeneration after acute pancreatitis
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DOI：
10.1053/j.gastro.2007.11.003
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发表时间：
2008-02-01
期刊：
影响因子：
29.4
通讯作者：
Schmid, Roland M.
中科院分区：
文献类型：
--
作者：
Sivere, Jens T.;Lubeseder-Martellato, Clara;Schmid, Roland M.
背景和目标：急性胰腺炎后组织再生和更新的机制还不清楚，但可能涉及Notch信号的激活。为了研究Notch信号消融在急性实验性胰腺炎中的作用，我们使用化学和遗传方法来消融雨蛙素诱导的小鼠胰腺炎中的Notch信号。研究方法：在用γ-分泌酶抑制剂dibenzazepine处理的小鼠或条件性Notch 1基因敲除小鼠中，通过雨蛙肽处理诱导急性胰腺炎。小鼠的特点是使用免疫组织学，生物化学和分子方法。为了研究Notch和β-连环蛋白的相互作用，使用转染和生物化学测定来分析腺泡266-6细胞。结果如下：Notch信号传导的缺失导致急性胰腺炎后再生受损，诱导后3天再生阶段二苯氮卓治疗和Notch 1缺陷小鼠中成熟腺泡细胞较少。β-连环蛋白表达在外分泌再生过程中增加并延长。Notch和β-连环蛋白介导的信号传导之间的串扰被鉴定，Notch 1-IC抑制β-连环蛋白介导的转录活性。这种抑制依赖于功能性RAM结构域。结论：体内Notch信号的抑制导致急性胰腺炎后胰腺外分泌再生受损。我们的研究结果表明，Notch和Writ信号在胰腺腺泡细胞中的相互作用，这些途径在调节腺泡细胞的成熟过程中的作用提供了证据。
Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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 Writ signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells.