Okamoto Ryuichi, Tsuchiya Kiichiro, Nemoto Yasuhiro, Akiyama Junko, Nakamura Tetsuya, Kanai Takanori, Watanabe Mamoru
Dept. of Advanced Therapeutics in Gastrointestinal Diseases, Graduate School, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Am J Physiol Gastrointest Liver Physiol. 2009 Jan;296(1):G23-35. doi: 10.1152/ajpgi.90225.2008. Epub 2008 Nov 20.
Notch signaling regulates cell differentiation and proliferation, contributing to the maintenance of diverse tissues including the intestinal epithelia. However, its role in tissue regeneration is less understood. Here, we show that Notch signaling is activated in a greater number of intestinal epithelial cells in the inflamed mucosa of colitis. Inhibition of Notch activation in vivo using a gamma-secretase inhibitor resulted in a severe exacerbation of the colitis attributable to the loss of the regenerative response within the epithelial layer. Activation of Notch supported epithelial regeneration by suppressing goblet cell differentiation, but it also promoted cell proliferation, as shown in in vivo and in vitro studies. By utilizing tetracycline-dependent gene expression and microarray analysis, we identified a novel group of genes that are regulated downstream of Notch1 within intestinal epithelial cells, including PLA2G2A, an antimicrobial peptide secreted by Paneth cells. Finally, we show that these functions of activated Notch1 are present in the mucosa of ulcerative colitis, mediating cell proliferation, goblet cell depletion, and ectopic expression of PLA2G2A, thereby contributing to the regeneration of the damaged epithelia. This study showed the critical involvement of Notch signaling during intestinal tissue regeneration, regulating differentiation, proliferation, and antimicrobial response of the epithelial cells. Thus Notch signaling is a key intracellular molecular pathway for the proper reconstruction of the intestinal epithelia.
Notch信号通路调节细胞分化和增殖，有助于维持包括肠道上皮在内的多种组织。然而，其在组织再生中的作用尚不清楚。在此，我们表明在结肠炎炎症黏膜中，更多的肠道上皮细胞中Notch信号通路被激活。使用γ-分泌酶抑制剂在体内抑制Notch激活，导致结肠炎严重恶化，这归因于上皮层内再生反应的丧失。体内和体外研究表明，Notch激活通过抑制杯状细胞分化支持上皮再生，但也促进细胞增殖。通过利用四环素依赖性基因表达和微阵列分析，我们鉴定出一组在肠道上皮细胞中受Notch1下游调控的新基因，包括潘氏细胞分泌的抗菌肽PLA2G2A。最后，我们表明激活的Notch1的这些功能存在于溃疡性结肠炎的黏膜中，介导细胞增殖、杯状细胞耗竭和PLA2G2A的异位表达，从而促进受损上皮的再生。这项研究表明Notch信号通路在肠道组织再生过程中起关键作用，调节上皮细胞的分化、增殖和抗菌反应。因此，Notch信号通路是肠道上皮正确重建的关键细胞内分子途径。
