Abstract
Organoid culture is an approach that allows three-dimensional growth for stem cells
to self-organize and develop multicellular structures. Intestinal organoids have been
widely used to study cellular or molecular processes in stem cell and cancer research.
These cultures possess the ability to maintain cellular complexity as well as recapitulate
many properties of the human intestinal epithelium, thereby providing an ideal in vitro model to investigate cellular and molecular signaling pathways. These include, but
are not limited to, the mechanisms required for maintaining balanced populations of
epithelial cells. Notch signaling is one of the major pathways of regulating stem
cell functions in the gut driving proliferation and controlling cell fate determination.
Notch also plays an important role in regulating tumor progression and metastasis.
Understanding how Notch pathway regulates epithelial regeneration and differentiation
by using intestinal organoids is critical for studying both homeostasis and pathogenesis
of intestinal stem cells (ISCs) that can lead to discoveries of new targets for drug
development to treat intestinal diseases. Additionally, use of patient-derived organoids
can provide effective personalized medicine. In this review, we summarize the current
literature regarding epithelial Notch pathways regulating intestinal homeostasis and
regeneration, highlighting the use of organoid cultures and their potential therapeutic
applications.
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References
- Long-term Expansion of Epithelial Organoids From Human Colon, Adenoma, Adenocarcinoma, and Barrett's Epithelium.Gastroenterology. 2011; 141: 1762-1772
- Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007
- OLFM4 Is a Robust Marker for Stem Cells in Human Intestine and Marks a Subset of Colorectal Cancer Cells.Gastroenterology. 2009; 137: 15-17
- Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate.Cell. 2009; 136: 903-912
- Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine.FEBS letters. 2003; 535: 131-135
- The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers.The EMBO Journal. 2012; 31: 3079-3091
- Extreme sensitivity of some intestinal crypt cells to X and γ irradiation.Nature. 1977; 269: 518-521
- The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations.Proceedings of the National Academy of Sciences. 2012; 109: 466-471
- Bmi1 is expressed in vivo in intestinal stem cells.Nature genetics. 2008; 40: 915-920
- Interconversion Between Intestinal Stem Cell Populations in Distinct Niches.Science. 2011; 334: 1420-1424
- Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells.Proceedings of the National Academy of Sciences. 2011; 108: 179-184
- The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor.Cell. 2012; 149: 146-158
- Intestinal label-retaining cells are secretory precursors expressing Lgr5.Nature. 2013; 495: 65-69
- Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters.Cell stem cell. 2016; 18: 203-213
- Dll1+ secretory progenitor cells revert to stem cells upon crypt damage.Nature Cell Biology. 2012; 14: 1099-1104
- A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable.Nature. 2011; 478: 255-259
- Phospho-regulation of ATOH1 Is Required for Plasticity of Secretory Progenitors and Tissue Regeneration.Cell stem cell. 2018; 23 (e7): 436-443
- Matrigel: a complex protein mixture required for optimal growth of cell culture.Proteomics. 2010; 10: 1886-1890
- Generating human intestinal tissue from pluripotent stem cells in vitro.Nature protocols. 2011; 6: 1920-1928
- Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro.Nature. 2011; 470: 105-109
- Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo.Stem Cell Reports. 2015; 4: 1140-1155
- Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity.Cell stem cell. 2017; 21 (78-90.e6)
- Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications.Science. 2013; 340: 1190-1194
- Isolation and in vitro expansion of human colonic stem cells.Nature medicine. 2011; 17: 1225-1227
- Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny.Nature methods. 2014; 11: 106-112
- Single-cell messenger RNA sequencing reveals rare intestinal cell types.Nature. 2015; 525: 251-255
- Wnt/beta-catenin signaling: components, mechanisms, and diseases.Developmental cell. 2009; 17: 9-26
- Expression pattern of Wnt signaling components in the adult intestine.Gastroenterology. 2005; 129: 626-638
- EGF signaling activates proliferation and blocks apoptosis of mouse and human intestinal stem/progenitor cells in long-term monolayer cell culture.Lab Invest. 2010; 90: 1425-1436
- Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors.Proceedings of the National Academy of Sciences of the United States of America. 2007; 104: 15418-15423
- De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine.Science. 2004; 303: 1684-1686
- The canonical Notch signaling pathway: unfolding the activation mechanism.Cell. 2009; 137: 216-233
- Notch as a Driver of Gastric Epithelial Cell Proliferation.Cell Mol Gastroenterol Hepatol. 2017; 3: 323-330
- Notch in the intestine: regulation of homeostasis and pathogenesis.Annu Rev Physiol. 2013; 75: 263-288
- The role of Hes genes in intestinal development, homeostasis and tumor formation.Development (Cambridge, England). 2012; 139: 1071-1082
- Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis.Gastroenterology. 2007; 132: 2478-2488
- Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors.Nature communications. 2010; 1: 18
- The cis side of juxtacrine signaling: a new role in the development of the nervous system.Trends Neurosci. 2012; 35: 230-239
- Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.Development. 2012; 139: 488-497
- Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells.Nature. 2005; 435: 959-963
- Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice.PLoS One. 2011; 6e25785
- Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration.Developmental biology. 2015; 402: 98-108
- Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.Gastroenterology. 2011; 140 (e1-7): 1230-1240
- ADAM10 regulates Notch function in intestinal stem cells of mice.Gastroenterology. 2014; 147 (e13): 822-834
- 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: 377-383
- Notch signalling regulates asymmetric division and inter-conversion between lgr5 and bmi1 expressing intestinal stem cells.Scientific reports. 2016; 626069
- Notch regulation of gastrointestinal stem cells.J Physiol. 2016; 594: 4791-4803
- Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells.Cell. 2010; 143: 134-144
- Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity.Nature. 2014; 506: 511-515
- Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265
- Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418
- A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.Mol Syst Biol. 2017; 13: 927
- Acquisition of NOTCH dependence is a hallmark of human intestinal stem cell maturation.Stem Cell Reports. 2022; 17: 1138-1153
- The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters.Development (Cambridge, England). 1999; 126: 3925-3935
- Cellular Plasticity of Defa4(Cre)-Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury.Cell Mol Gastroenterol Hepatol. 2019; 7: 533-554
- Requirement of Notch activation during regeneration of the intestinal epithelia.American journal of physiology Gastrointestinal and liver physiology. 2009; 296 1: G23-35
- Paneth Cells Respond to Inflammation and Contribute to Tissue Regeneration by Acquiring Stem-like Features through SCF/c-Kit Signaling.Cell reports. 2018; 24 (e7): 2312-2328
- Use of organoids to study regenerative responses to intestinal damage.Am J Physiol Gastrointest Liver Physiol. 2019; 317 (G845-g52)
- Cycling Stem Cells Are Radioresistant and Regenerate the Intestine.Cell reports. 2020; 32107952
- Radiation-induced Notch signaling in breast cancer stem cells.Int J Radiat Oncol Biol Phys. 2013; 87: 609-618
- Notch is a direct negative regulator of the DNA-damage response.Nat Struct Mol Biol. 2015; 22: 417-424
- Paneth Cell Multipotency Induced by Notch Activation following Injury.Cell stem cell. 2018; 23 (e5): 46-59
- Contribution of ATOH1(+) Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium.Stem Cell Reports. 2018; 10: 27-42
- Atoh1(+) secretory progenitors possess renewal capacity independent of Lgr5(+) cells during colonic regeneration.Embo j. 2019; 38e99984
- Targeting p53-dependent stem cell loss for intestinal chemoprotection.Sci Transl Med. 2018; 10eaam7610
- Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.Scientific reports. 2015; 5: 8566
- Organoid-based modeling of intestinal development, regeneration, and repair.Cell death and differentiation. 2021; 28: 95-107
- YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.Cell stem cell. 2018; 22 (e7): 35-49
- A gp130-Src-YAP module links inflammation to epithelial regeneration.Nature. 2015; 519: 57-62
- Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche.Nature. 2018; 559: 109-113
- Activation of Notch signaling in human colon adenocarcinoma.Int J Oncol. 2008; 33: 1223-1229
- A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis.Cell stem cell. 2016; 18: 827-838
- High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53.Proceedings of the National Academy of Sciences of the United States of America. 2021; : 118
- Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut.Nature communications. 2014; 5: 5005
- Colorectal cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 145-164
- Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis.Cancer Cell. 2019; 36 (e7): 319-336
- AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer.J Exp Med. 2020; : 217
- Notch3 signalling promotes tumour growth in colorectal cancer.The Journal of pathology. 2011; 224: 448-460
- Prospective derivation of a living organoid biobank of colorectal cancer patients.Cell. 2015; 161: 933-945
- Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.Science. 2018; 359: 920-926
- Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer.Scientific reports. 2018; 8: 3335
- A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors.Annals of Oncology. 2018; 29: 1561-1568
- A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors.Investigational New Drugs. 2019; 37: 722-730
- Interleukin-22: Immunobiology and Pathology.Annual Review of Immunology. 2015; 33: 747-785
- Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.Nature. 2015; 528: 560-564
- Adhesive Interactions between Mononuclear Phagocytes and Intestinal Epithelium Perturb Normal Epithelial Differentiation and Serve as a Therapeutic Target in Inflammatory Bowel Disease.J Crohns Colitis. 2018; 12: 1219-1231
- Human Intestinal Organoids Maintain Self-Renewal Capacity and Cellular Diversity in Niche-Inspired Culture Condition.Cell stem cell. 2018; 23 (787-93.e6)
- The role of notch signaling in endothelial progenitor cell biology.Trends Cardiovasc Med. 2009; 19: 170-173
- Notch signaling in the immune system.Immunity. 2010; 32: 14-27
- Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses.Frontiers in immunology. 2018; 9: 1288
- An in vivo model of human small intestine using pluripotent stem cells.Nature medicine. 2014; 20: 1310-1314
- Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients.Cell stem cell. 2013; 13: 653-658
Article Info
Publication History
Accepted:
June 7,
2022
Received in revised form:
May 16,
2022
Received:
March 9,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Sources of support: This work was supported in part by research funding from NCI CA222064 and NIH HL103827 (to LZ), and by the Department of Pathology Case Western Reserve University faculty startup fund to LZ.
Disclosure of Potential Conflicts of Interest: The authors have declared that no conflict of interest exists.
Identification
Copyright
© 2022 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
