Requirement of Notch activation during regeneration of the intestinal epithelia
- 1 January 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 296 (1), G23-G35
- https://doi.org/10.1152/ajpgi.90225.2008
Abstract
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 γ-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.Keywords
This publication has 38 references indexed in Scilit:
- Gastrointestinal Stem Cells. II. Intestinal stem cellsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2005
- Notch signals control the fate of immature progenitor cells in the intestineNature, 2005
- Increase of Bone Marrow–Derived Secretory Lineage Epithelial Cells During Regeneration in the Human IntestineGastroenterology, 2005
- Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitisClinical and Experimental Immunology, 2003
- Modulation of specific intestinal epithelial progenitors by enteric neuronsProceedings of the National Academy of Sciences of the United States of America, 2001
- Coordinated localisation of mucins and trefoil peptides in the ulcer associated cell lineage and the gastrointestinal mucosaGut, 2000
- The antibacterial properties of secreted phospholipases A2Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2000
- Control of endodermal endocrine development by Hes-1Nature Genetics, 2000
- Phospholipase A2 in serum and colonic mucosa in ulcerative colitisScandinavian Journal of Clinical and Laboratory Investigation, 1999
- Gene expression of group II phospholipase A2 in intestine in ulcerative colitis.Gut, 1997