Requirement of Notch activation during regeneration of the intestinal epithelia.
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.
Okamoto
Ryuichi
R
Dept. of Advanced Therapeutics in Gastrointestinal Diseases, Graduate School, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Tsuchiya
Kiichiro
K
Nemoto
Yasuhiro
Y
Akiyama
Junko
J
Nakamura
Tetsuya
T
Kanai
Takanori
T
Watanabe
Mamoru
M
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D054501:Group II Phospholipases A2 / Q000378:metabolism; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1
D000409:Alanine; D053829:Amyloid Precursor Protein Secretases; D001381:Azepines; D051792:Basic Helix-Loop-Helix Proteins; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors; D054501:Group II Phospholipases A2; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C078493:HES1 protein, human; C516287:PLA2G2A protein, human