Generic placeholder image

Current Stem Cell Research & Therapy


ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

Notch Signaling in Mammalian Intestinal Stem Cells: Determining Cell Fate and Maintaining Homeostasis

Author(s): Shao-jie Liang, Xiang-guang Li and Xiu-qi Wang*

Volume 14, Issue 7, 2019

Page: [583 - 590] Pages: 8

DOI: 10.2174/1574888X14666190429143734

Price: $65


The intestine serves mainly as a place for digestion and absorption and functions as an immune and endocrine organ. Intestinal stem cells (ISCs) play critical roles in the maintenance of intestinal homeostasis and regeneration, and a complex of signaling pathways is involved in these processes. The Notch signaling pathway is induced via distinct cell-to-cell connections, which are activated through the binding of the Notch ligand on the surface of niche cells to the Notch receptor on ISCs. Numerous studies have shown the central importance of Notch signaling in the proliferation and differentiation of ISCs. Here, we summarize the latest research progress on the crucial functions of Notch signaling in maintaining homeostasis and determining the cell fate of ISCs. Furthermore, the challenges of Notch signaling in colon cancer therapy strategies are also discussed. Several important questions regarding Notch regulation of ISCs are proposed.

Keywords: Notch signaling, cell fate decision, intestinal stem cells, Paneth cells, Hes1, Atoh1.

Barker N, Van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003-7.
Rizk P, Barker N. Gut stem cells in tissue renewal and disease: Methods, markers, and myths. Wires Syst Biol Med 2012; 4: 475-96.
Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008; 40: 915-20.
Li CM, Yan HC, Fu HL, et al. Molecular cloning, sequence analysis, and function of the intestinal epithelial stem cell marker Bmi1 in pig intestinal epithelial cells. J Anim Sci 2014; 92(1): 85-94.
Li XG, Wang Z, Chen RQ, et al. Lgr5 and Bmi1 Increase Pig Intestinal Epithelial Cell Proliferation by Stimulating WNT/β-Catenin Signaling. Int J Mol Sci 2018; 19(4): 1036.
Barker N. Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 2014; 15(1): 19-33.
Sailaja BS, He XC, Li L. The regulatory niche of intestinal stem cells. J Physiol 2016; 594(17): 4827-36.
Van Es JH, Sato T, van de Wetering M, et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 2012; 14: 1099-104.
Miyazono K, Kamiya Y, Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem 2010; 147(1): 35-51.
Kosinski C, Stange DE, Xu C, et al. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 2010; 139: 893-903.
Li XG, Zhu M, Chen MX, et al. Acute exposure to deoxynivalenol inhibits porcine enteroid activity via suppression of the Wnt/β-catenin pathway. Toxicol Lett 2019; 305: 19-31.
Zhou JY, Huang DG, Qin YC, et al. mTORC1 signaling activation increases intestinal stem cell activity and promotes epithelial cell proliferation. J Cell Physiol 2019; 234(10): 19028-38.
Demitrack ES, Samuelson LC. Notch regulation of gastrointestinal stem cells. J Physiol 2016; 594(17): 4791-803.
Kopan R, Ilagan MX. The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell 2009; 137: 216-33.
Bray SJ. Notch signaling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006; 7: 678-89.
Allenspach EJ, Maillard I, Aster JC, Pear WS. Notch Signaling in Cancer. Cancer Biol Ther 2002; 1: 466-76.
Noah TK, Shroyer NF. Notch in the intestine: Regulation of homeostasis and pathogenesis. Annu Rev Physiol 2013; 75: 263-88.
Guruharsha KG, Kankel MW, Spyros AT. The Notch signaling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 2012; 13: 654-66.
Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev 2017; 97: 1235-94.
Sander GR, Powell BC. Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem 2004; 52: 509-16.
Schröder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns 2002; 2: 247-50.
Silvia F, Mathilde H, Philippos M, Sylvie R, Daniel L, Spyros AT. Notch signals control the fate of immature progenitor cells in the intestine. Nature 2005; 435: 964-8.
Van Es JH, Van Gijn ME, Riccio O, et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005; 435(7044): 959-63.
Fre S, Hannezo E, Sale S, et al. Notch Lineages and Activity in Intestinal Stem Cells Determined by a New Set of Knock-In Mice. PLoS One 2011; 6e25785
Riccio O, Van Gijn ME, Bezdek AC, et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 2008; 9(4): 377-83.
Carulli AJ, Keeley TM, Demitrack ES, et al. Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration. Dev Biol 2015; 402: 98-108.
Tran IT, Sandy AR, Carulli AJ, et al. Blockade of individual Notch ligands and receptors control graft-versus-host disease. J Clin Invest 2013; 123: 1590-604.
Van ES, Johan H, Sato T, Marc VDW, et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 2012; 14(10): 1099-104.
Pellegrinet L, Rodilla V, Liu Z, et al. Dll1- and Dll4-Mediated Notch Signaling Are Required for Homeostasis of Intestinal Stem Cells. Gastroenterology 2011; 140: 1230-40.
Shimizu H, Okamoto R, Ito G, et al. Distinct expression patterns of Notch ligands, Dll1 and Dll4, in normal and inflamed mice intestine. PeerJ 2014; 2e370
VanDussen KL, Carulli AJ, Keeley TM, et al. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 2012; 139: 488-97.
Milano J, Mckay J, Dagenais C, et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 2004; 82: 341-58.
Wong GT, Manfra D, Frederique MP, et al. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279: 12876-82.
Dyczynska E, Sun D, Yi H, Sehara-Fujisawa A, Blobel CP, Zolkiewska A. Proteolytic processing of delta-like 1 by ADAM proteases. J Biol Chem 2007; 282: 436-44.
Zolkiewska A. ADAM proteases: Ligand processing and modulation of the Notch pathway. Cell Mol Life Sci 2008; 65: 2056-68.
Hideyuki S, Woodcock SA, Wilkin MB, Barbora T, Monk NAM, Martin B. Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 2014; 157: 1160-74.
Tsai YH, Vandussen KL, Sawey ET, et al. ADAM10 regulates Notch function in intestinal stem cells of mice. Gastroenterology 2014; 147: 822-34.
Dempsey PJ. Role of ADAM10 in Intestinal Crypt Homeostasis and Tumorigenesis. BBA-Mol Cell Res 2017; 1864(11 Pt B): 2228-39.
Rustagi S, Jones JC, Tsai YH, et al. ADAM10-Mediated Notch Signaling Is Essential for Maintenance of BMI1+ Intestinal Stem Cells (ISCs). Gastroenterology 2015; 148: S-106.
Feng YJ, Tsai YH, Xiao WD, et al. Loss of ADAM17-mediated tumor necrosis factor alpha signaling in intestinal cells attenuates mucosal atrophy in a mouse model of parenteral nutrition. Mol Cell Biol 2015; 35: 3604-21.
Panin VM, Papayannopoulos V, Wilson R, Irvine KD. Fringe modulates Notch-ligand interactions. Nature 1997; 387: 908-12.
Moloney DJ, Panin VM, Johnston SH, et al. Fringe is a glycosyltransferase that modifies Notch. Nature 2015; 406: 369-75.
Kadur LMP, Srinivasan T, Bochter MS, et al. Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis. eLife 2018; 7e35710
Nichols JT, Miyamoto A, Weinmaster G. Notch signaling constantly on the move. Traffic 2007; 8: 959-69.
Gulino A, Di ML, Screpanti I. The multiple functions of Numb. Exp Cell Res 2010; 316: 900-6.
Yang YT, Zhu R, Bai JY, et al. Numb modulates intestinal epithelial cells toward goblet cell phenotype by inhibiting the Notch signaling pathway. Exp Cell Res 2011; 317: 1640-8.
Bu P, Wang L, Chen KY, et al. A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer. Cell Stem Cell 2016; 18: 189-202.
Suzuki K, Fukui H, Kayahara T, et al. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. Biochem Bioph res Co 2005; 328: 348-52.
Ueo T, Imayoshi I, Kobayashi T, et al. The role of Hes genes in intestinal development, homeostasis and tumor formation. Development 2012; 139: 1071-82.
Sancho R, Blake SM, Tendeng C, Clurman BE, Lewis J, Behrens A. Fbw7 repression by hes5 creates a feedback loop that modulates Notch-mediated intestinal and neural stem cell fate decisions. PLoS Biol 2013; 11e1001586
Liu Z, Li L, Chen W, et al. Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway. Int J Mol Med 2018; 41: 1560-72.
Pope JL, Bhat AA, Ashok S, et al. Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signaling. Gut 2014; 63: 622-34.
Ming XH, Yu T, Qing Q, et al. Abnormal differentiation of intestinal epithelium and intestinal barrier dysfunction in diabetic mice associated with depressed Notch/NICD transduction in Notch/Hes1 signal pathway. Cell Biol Int 2015; 38: 1194-204.
Kazanjian A, Noah T, Brown D, Burkart J, Shroyer NF. Atonal homolog 1 is required for growth and differentiation effects of notch/gamma-secretase inhibitors on normal and cancerous intestinal epithelial cells. Gastroenterology 2010; 139: 918-28.
Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 2001; 294: 2155-8.
Zheng X, Tsuchiya K, Okamoto R, et al. Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis 2011; 17: 2251-60.
Collier JR, Monk NAM, Maini PK, Lewis JH. Pattern Formation by Lateral Inhibition with Feedback: A Mathematical Model of Delta-Notch Intercellular Signaling. J Theor Biol 1996; 183: 429-46.
Sancho R, Cremona CA, Behrens A. Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease. EMBO Rep 2015; 16: 571-81.
Chen KY, Srinivasan T, Tung KL, et al. A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal. Mol Syst Biol 2017; 13(4): 927.
Lähdeniemi IAK, Misiorek JO, Antila CJM, et al. Keratins regulate colonic epithelial cell differentiation through the Notch1 signaling pathway. Cell Death Differ 2017; 24(6): 984-96.
Robinson SC, Klobucar K, Pierre CC, et al. Kaiso differentially regulates components of the Notch signaling pathway in intestinal cells. Cell Commun Signal 2017; 15: 24.
Yin L, Velazquez OC, Liu ZJ. Notch signaling: Emerging molecular targets for cancer therapy. Biochem Pharmacol 2010; 80: 690-701.
Fre S, Pallavi SK, Huyghe M, et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 2009; 106: 6309-14.
Nakata T, Shimizu H, Nagata S, et al. Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. Biochem Biophys Res Commun 2017; 482(4): 1296-303.
Sikandar SS, Pate KT, Anderson S, et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res 2010; 70: 1469-78.
McCarthy JV, Twomey C, Wujek P. Presenilin-dependent regulated intra-membrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 2009; 66: 1534-55.
Wu Y, Cain-Hom C, Choy L, et al. Therapeutic antibody targeting of individual Notch receptors. Nature 2010; 464: 1052-7.
Atapattu L, Saha N, Chheang C, et al. An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. J Exp Med 2016; 213: 1741-57.
Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009; 459: 262-5.
Date S, Sato T. Mini-gut organoids: Reconstitution of the stem cell niche. Annu Rev Cell Dev Biol 2015; 31: 269-89.
Wang F, Scoville D, He XC, et al. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 2013; 145: 383-95.
Yin XL, Farin HF, van Es JH, et al. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat Methods 2014; 11: 106-12.
Basak O, Beumer J, Wiebrands K, et al. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell 2016; 20: 177-90.
Tian H, Biehs B, Chiu C, et al. Opposing activities of notch and wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 2015; 11: 33-42.
Katoh M, Katoh M. Notch ligand, JAG1, is the evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med 2006; 17: 681-5.
Rodilla V, Villanueva A, Obrador-Hevia A, et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA 2009; 106: 6315-20.
Farin HF, Es JH. Van, Hans C. Redundant sources of Wnt regulate intestinal stem cells and promote the formation of Paneth cells. Gastroenterology 2012; 143: 1518-29.
Despina S, Maxine H, Christine H, et al. Delta1 expression, cell cycle exit, and commitment to a specific secretory fate coincide within a few hours in the mouse intestinal stem cell system. PLoS One 2011; 6e24484
Smith NR, Swain JR, Davies PS, et al. Monoclonal antibodies reveal dynamic plasticity between Lgr5- and Bmi1-expressing intestinal cell populations. Cell Mol Gastroenterol Hepatol 2018; 6: 79-96.
Yang WH, Bengtsson RJ, Macintyre N, et al. Lawsonia intracellularisexploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation. PLoS One 2017; 12e0173782
Wongchana W, Kongkavitoon P, Tangtanatakul P, et al. Notch signaling regulates the responses of lipopolysaccharide-stimulated macrophages in the presence of immune complexes. PLoS One 2018; 13e0198609
Peregrina K, Houston M, Daroqui C, et al. Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions. Carcinogenesis 2015; 36: 25-31.
Demitrack ES, Gifford GB, Keeley TM, et al. Notch signaling regulates gastric antral LGR5 stem cell function. EMBO J 2015; 34: 2522-36.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy