Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis
Open accessAbstract
Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The increase in secretory lineage cells in aged intestinal stem cells implies deregulation of stem cell differentiation pathways in aged ISCs, most likely as a response to deregulated Notch signaling (e.g., elevated Atoh1).
“The increase in the number of secretory lineage cells, namely Paneth and goblet cells, also implies deregulation of stem cell differentiation pathways in aged ISCs, most likely as a response to deregulated Notch signaling, like elevated levels of Atoh1 expression (Kim et al., 2014; Koch et al., 2013; Tian et al., 2015).”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Tian et al., 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Identification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687 · see citing works
Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Sato, T., van Es, J. H., Snippert, H. J., Stange, D. E., Vries, R. G., van den Born, M., Barker, N., Shroyer, N. F., van de Wetering, M., & Clevers, H. (2011) · Nature · doi:10.1038/nature09637 · Cited by 2,510 · see citing works
Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4
Kořínek, V., Barker, N., Moerer, P., van Donselaar, E. V., Huls, G., Peters, P., & Clevers, H. (1998) · Nature Genetics · doi:10.1038/1270 · Cited by 1,704 · see citing works
van Es, J. H., van Gijn, M. E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D. J., Radtke, F., et al. (2005) · Nature · doi:10.1038/nature03659 · Cited by 1,541 · see citing works
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling
de Lau, W., Barker, N., Low, T. Y., Koo, B., Li, V. S. W., Teunissen, H., Kujala, P., Haegebarth, A., Peters, P. J., van de Wetering, M., et al. (2011) · Nature · doi:10.1038/nature10337 · Cited by 1,267 · see citing works
Canonical Wnt signals are essential for homeostasis of the intestinal epithelium
Pinto, D., Gregorieff, A., Begthel, H., & Clevers, H. (2003) · Genes & Development · doi:10.1101/gad.267103 · Cited by 1,026 · see citing works
Notch1 functions as a tumor suppressor in mouse skin
Nicolas, M., Wolfer, A., Raj, K., Kummer, J. A., Mill, P., van Noort, M., Hui, C., Clevers, H. C., Dotto, G. P., & Radtke, F. (2003) · Nature Genetics · doi:10.1038/ng1099 · Cited by 969 · see citing works
Notch signals control the fate of immature progenitor cells in the intestine
Fré, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., & Artavanis‐Tsakonas, S. (2005) · Nature · doi:10.1038/nature03589 · Cited by 936 · see citing works
Requirement of Math1 for Secretory Cell Lineage Commitment in the Mouse Intestine
Yang, Q., Bermingham, N. A., Finegold, M. J., & Zoghbi, H. Y. (2001) · Science · doi:10.1126/science.1065718 · Cited by 919 · see citing works
Epidermal Stem Cells of the Skin
Blanpain, C., & Fuchs, E. V. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104357 · Cited by 845 · see citing works
Intestinal label-retaining cells are secretory precursors expressing Lgr5
Buczacki, S. J. A., Zecchini, H. I., Nicholson, A. M., Russell, R., Vermeulen, L., Kemp, R., & Winton, D. J. (2013) · Nature · doi:10.1038/nature11965 · Cited by 761 · see citing works
Therapeutic antibody targeting of individual Notch receptors
Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J. B., et al. (2010) · Nature · doi:10.1038/nature08878 · Cited by 713 · see citing works
Self-citationRedundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells
Farin, H. F., Van Es, J. H., & Clevers, H. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.08.031 · Cited by 655 · see citing works
Wnt signalling induces maturation of Paneth cells in intestinal crypts
van Es, J. H., Jay, P., Gregorieff, A., van Gijn, M. E., Jonkheer, S. M., Hatzis, P., Thiele, A., van den Born, M., Begthel, H., Brabletz, T., et al. (2005) · Nature Cell Biology · doi:10.1038/ncb1240 · Cited by 651 · see citing works
Wnt/β-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells
Fevr, T., Robine, S., Louvard, D., & Huelsken, J. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01034-07 · Cited by 650 · see citing works
Expression Pattern of Wnt Signaling Components in the Adult Intestine
Gregorieff, A., PINTO, D., Begthel, H., Destrée, O., Kielman, M. F., & Clevers, H. C. (2005) · Gastroenterology · doi:10.1016/j.gastro.2005.06.007 · Cited by 615 · see citing works
VanDussen, K. L., Carulli, A. J., Keeley, T. M., Patel, S. R., Puthoff, B. J., Magness, S. T., Tran, I., Maillard, I. P., Siebel, C. W., Kolterud, Å., et al. (2011) · Development · doi:10.1242/dev.070763 · Cited by 579 · see citing works
Self-citationAndreu, P., Colnot, S., Godard, C., Gad, S., Chafey, P., Niwa‐Kawakita, M., Laurent‐Puig, P., Kahn, A., Robine, S., Perret, C., et al. (2005) · Development · doi:10.1242/dev.01700 · Cited by 291 · see citing works
A Critical Role for the Wnt Effector Tcf4 in Adult Intestinal Homeostatic Self-Renewal
van Es, J. H., Haegebarth, A., Kujala, P., Itzkovitz, S., Koo, B., Boj, S. F., Korving, J., van den Born, M., van Oudenaarden, A., Robine, S., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06288-11 · Cited by 271 · see citing works
R-Spondin Proteins: A Novel Link to β-catenin Activation
Kim, K., Zhao, J., Andarmani, S., Kakitani, M., Oshima, T., Binnerts, M. E., Abo, A., Tomizuka, K., & Funk, W. D. (2005) · Cell Cycle · doi:10.4161/cc.5.1.2305 · Cited by 252 · see citing works
R-Spondin Potentiates Wnt/β-Catenin Signaling through Orphan Receptors LGR4 and LGR5
Ruffner, H., Sprunger, J., Charlat, O., Leighton-Davies, J. R., Grosshans, B. L., Salathe, A., Zietzling, S., Beck, V., Therier, M., Isken, A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040976 · Cited by 170 · see citing works
Ireland, H., Houghton, C. A., Howard, L., & Winton, D. J. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20446 · Cited by 139 · see citing works
VanDussen, K. L., & Samuelson, L. C. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.07.026 · Cited by 138 · see citing works
Shi, F., Cheng, Y., Wang, X. L., & Edge, A. S. B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.059055 · Cited by 118 · see citing works
Kim, T., & Shivdasani, R. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.188797 · Cited by 96 · see citing works
Kazanjian, A. A., Noah, T. K., Brown, D., Burkart, J. T., & Shroyer, N. F. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.05.081 · Cited by 92 · see citing works
Lrp5 and Lrp6 play compensatory roles in mouse intestinal development
Zhong, Z. A., Baker, J. J., Diegel, C. R., & Williams, B. O. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23324 · Cited by 59 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tales from the crypt: new insights into intestinal stem cells
Gehart, H., & Clevers, H. C. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0081-y · Cited by 984 · see citing works
The intestinal barrier: a pivotal role in health, inflammation, and cancer
Neurath, M. F., Artis, D., & Becker, C. (2025) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(24)00390-x · Cited by 512 · see citing works
Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
Cheng, C., Biton, M., Haber, A. L., Gündüz, N., Eng, G. M., Gaynor, L. T., Tripathi, S. M., Calibasi‐Kocal, G., Rickelt, S., Butty, V. L., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.048 · Cited by 371 · see citing works
Fan, P. F., Liu, P., Song, P., Chen, X., & Ma, X. (2017) · Scientific Reports · doi:10.1038/srep43412 · Cited by 354 · see citing works
Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances
Chen, X., Chu, Q., Shi, Q., Zeng, Y., Lu, J., & Li, . (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02142-w · Cited by 321 · see citing works
Phenotypic landscape of intestinal organoid regeneration
Lukonin, I., Serra, D., Challet Meylan, L., Volkmann, K., Baaten, J., Zhao, R., Meeusen, S., Colman, K., Maurer, F., Stadler, M. B., et al. (2020) · Nature · doi:10.1038/s41586-020-2776-9 · Cited by 283 · see citing works
Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells
Nalapareddy, K., Nattamai, K. J., Kumar, R. S., Karns, R., Wikenheiser-Brokamp, K. A., Sampson, L. L., Mahe, M. M., Sundaram, N., Yacyshyn, M.-B., Yacyshyn, B., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.056 · Cited by 280 · see citing works
Yang, K., Wang, X., Zhang, H., Wang, Z., Nan, G., Li, Y., Zhang, F., Mohammed, M. K., Haydon, R. C., Luu, H. H., et al. (2015) · Laboratory Investigation · doi:10.1038/labinvest.2015.144 · Cited by 241 · see citing works
Morphogenesis and maturation of the embryonic and postnatal intestine
Chin, A. M., Hill, D. R., Aurora, M., & Spence, J. R. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.01.011 · Cited by 222 · see citing works
Herath, M., Hosie, S., Bornstein, J. C., Franks, A. E., & Hill‐Yardin, E. L. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00248 · Cited by 214 · see citing works
Signaling in the stem cell niche: regulating cell fate, function and plasticity
Chacón‐Martínez, C. A., Koester, J., & Wickström, S. A. (2018) · Development · doi:10.1242/dev.165399 · Cited by 193 · see citing works
Reserve Stem Cells in Intestinal Homeostasis and Injury
Bankaitis, E. D., Ha, A., Kuo, C. J., & Magness, S. T. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.08.016 · Cited by 187 · see citing works
Intestinal Stem Cell Aging: Origins and Interventions
Jasper, H. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034359 · Cited by 178 · see citing works
Jardé, T., Chan, W. H., Rossello, F. J., Kahlon, T. K., Theocharous, M., Arackal, T. K., Flores, T. J., Giraud, M., Richards, E., Chan, E., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.06.021 · Cited by 156 · see citing works
A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition
Biehs, B., Dijkgraaf, G. J. P., Piskol, R., Alicke, B., Boumahdi, S., Peale, F., Gould, S. E., & de Sauvage, F. J. (2018) · Nature · doi:10.1038/s41586-018-0596-y · Cited by 137 · see citing works
Self-citationMahapatro, M., Foersch, S., Hefele, M., He, G.-W., Giner-Ventura, E., Mchedlidze, T., Kindermann, M., Vetrano, S., Danese, S., Günther, C., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.049 · Cited by 125 · see citing works
Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer
Spit, M., Koo, B., & Maurice, M. M. (2018) · Open Biology · doi:10.1098/rsob.180120 · Cited by 120 · see citing works
Gastrointestinal stem cells in health and disease: from flies to humans
Li, H., & Jasper, H. (2016) · Disease Models & Mechanisms · doi:10.1242/dmm.024232 · Cited by 123 · see citing works
Zhao, L., Ben-Yair, R., Burns, C. E., & Burns, C. G. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.048 · Cited by 125 · see citing works
R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
Hayase, E., Hashimoto, D., Nakamura, K., Noizat, C., Ogasawara, R., Takahashi, S., Ohigashi, H., Yokoi, Y., Sugimoto, R., Matsuoka, S., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170418 · Cited by 120 · see citing works
The regulatory niche of intestinal stem cells
Sailaja, B. S., He, X., & Li, L. (2016) · The Journal of Physiology · doi:10.1113/jp271931 · Cited by 115 · see citing works
PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance
Baghdadi, M. B., Houtekamer, R. M., Perrin, L., Rao‐Bhatia, A., Whelen, M., Decker, L., Bergert, M., Gonzalez, C. P., Bouras, R., Gropplero, G., et al. (2024) · Science · doi:10.1126/science.adj7615 · Cited by 115 · see citing works
Chen, X., Song, P., Fan, P. F., He, T., Jacobs, D. R., Levesque, C. L., Johnston, L. J., Ji, L., Ma, N., Chen, Y., et al. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00246 · Cited by 106 · see citing works
Kim, J., Fei, L., Yin, W.-C., Coquenlorge, S., Rao‐Bhatia, A., Zhang, X., Shi, S. S. W., Lee, J. H., Hahn, N. A., Rizvi, W., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14058-5 · Cited by 103 · see citing works
Zha, J., Li, H.-S., Lin, Q., Kuo, W., Jiang, Z., Tsai, P.-Y., Ding, N., Jia Rui, W. U., Xu, S.-F., Wang, Y., et al. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.09.006 · Cited by 106 · see citing works
The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis
Peng, S., Shen, L., Yu, X., Zhang, L., Xu, K., Xia, Y., Zha, L., Wu, J., & Luo, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1200111 · Cited by 103 · see citing works
Dclk1-expressing tuft cells: critical modulators of the intestinal niche?
Middelhoff, M. A., Westphalen, C. B., Hayakawa, Y., Yan, K. S., Gershon, M. D., Wang, T. C., & Quante, M. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00073.2017 · Cited by 97 · see citing works
Notch signaling regulates gastric antral LGR5 stem cell function
Demitrack, E. S., Gifford, G. B., Keeley, T. M., Carulli, A. J., VanDussen, K. L., Thomas, D. G., Giordano, T. J., Liu, Z., Kopan, R., & Samuelson, L. C. (2015) · The EMBO Journal · doi:10.15252/embj.201490583 · Cited by 100 · see citing works
Notch signalling: multifaceted role in development and disease
Sachan, N., Sharma, V., Mutsuddi, M., & Mukherjee, A. (2023) · FEBS Journal · doi:10.1111/febs.16815 · Cited by 103 · see citing works
Kim, J., Li, B., Fei, L., Horne, R. G., Lee, D., Loe, A. K. H., Miyake, H., Ayar, E., Gurma, M., Kim, D., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.11.003 · Cited by 92 · see citing works
Chng, S. H., Kundu, P., Dominguez‐Brauer, C., Teo, W. L., Kawajiri, K., Fujii‐Kuriyama, Y., Mak, T. W., & Pettersson, S. (2016) · Scientific Reports · doi:10.1038/srep23820 · Cited by 89 · see citing works
Activation of fetal-like molecular programs during regeneration in the intestine and beyond
Viragova, S., Li, D., & Klein, O. D. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.05.009 · Cited by 88 · see citing works
Self-citationA selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells
Nile, A. H., Melo, F. D. S. E., Mukund, S., Piskol, R., Hansen, S., Zhou, L., Zhang, Y., Fu, Y., Gogol, E. B., Kömüves, L. G., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0035-2 · Cited by 82 · see citing works
Hohman, L. S., & Osborne, L. C. (2022) · Aging Cell · doi:10.1111/acel.13700 · Cited by 83 · see citing works
Notch Signaling in Pancreatic Development
Li, X., Zhai, W., & Teng, C.-B. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms17010048 · Cited by 64 · see citing works
Jang, D. S., Shin, J., Shim, E., Ohtani, N., & Jeon, O. H. (2024) · Aging Cell · doi:10.1111/acel.14315 · Cited by 84 · see citing works
Holmberg, F., Seidelin, J. B., Yin, X., Mead, B. E., Tong, Z., Li, Y., Karp, J. M., & Nielsen, O. H. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607260 · Cited by 78 · see citing works
Injury-Induced Cellular Plasticity Drives Intestinal Regeneration
Meyer, A. R., Brown, M. E., McGrath, P. S., & Dempsey, P. J. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.12.005 · Cited by 77 · see citing works
Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals
Kurokawa, K., Hayakawa, Y., & Koike, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010357 · Cited by 76 · see citing works
Stem Cell Signaling Pathways in the Small Intestine
Takahashi, T., & Shiraishi, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062032 · Cited by 75 · see citing works
ADAM Proteases and Gastrointestinal Function
Jones, J. C., Rustagi, S., & Dempsey, P. J. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021014-071720 · Cited by 73 · see citing works
Yun, J., Hansen, S., Morris, O., Madden, D. T., Libeu, C. P., Kumar, A. J., Wehrfritz, C., Nile, A. H., Zhang, Y., Zhou, L., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35487-9 · Cited by 75 · see citing works
SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation
Li, C., Zhou, Y., Rychahou, P. G., Weiss, H. L., Lee, E. Y., Perry, C. L., Barrett, T. A., Wang, Q., & Evers, B. M. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.01.004 · Cited by 72 · see citing works
Role of Notch signaling pathway in pancreatic cancer.
Gao, J., Long, B., & Wang, Z. P. (2017) · Europe PMC (PubMed Central) · Cited by 72 · see citing works
The development of a functional human small intestinal epithelium model for drug absorption
Kwon, O., Jung, K. B., Lee, K., Son, Y. S., Lee, H., Kim, J.-J., Kim, K., Lee, S., Song, Y.-K., Jung, J., et al. (2021) · Science Advances · doi:10.1126/sciadv.abh1586 · Cited by 70 · see citing works
Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche
Wang, Y., Kim, R., Hinman, S. S., Zwarycz, B., Magness, S. T., & Allbritton, N. L. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.01.008 · Cited by 70 · see citing works
Aging of intestinal stem cells
Nalapareddy, K., Zheng, Y., & Geiger, H. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.02.003 · Cited by 69 · see citing works
Source and Impact of the EGF Family of Ligands on Intestinal Stem Cells
Abud, H. E., Chan, W. H., & Jardé, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.685665 · Cited by 65 · see citing works
The interaction of Notch and Wnt signaling pathways in vertebrate regeneration
Gao, J., Fan, L., Zhao, L., & Su, Y. (2021) · Cell Regeneration · doi:10.1186/s13619-020-00072-2 · Cited by 63 · see citing works
CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation
Won, J. H., Choi, J. S., & Jun, J.-I. (2022) · Nature Communications · doi:10.1038/s41467-022-30851-1 · Cited by 59 · see citing works
Znhit1 controls intestinal stem cell maintenance by regulating H2A.Z incorporation
Zhao, B. T., Chen, Y., Jiang, N., Yang, L. C., Sun, S., Zhang, Y., Wen, Z., Ray, L., Liu, H., Hou, G., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09060-w · Cited by 58 · see citing works
NAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
Yang, L., Ruan, Z., Lin, X., Wang, H., Xin, Y., Tang, H., Hu, Z., Zhou, Y., Wu, Y., Wang, J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44808-z · Cited by 60 · see citing works
Self-citationWu, H., Ye, L., Lu, X., Xie, S., Yang, Q., & Yu, Q. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800552 · Cited by 58 · see citing works
Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells
Romera‐Hernández, M., Aparicio‐Domingo, P., Papazian, N., Karrich, J. J., Cornelissen, F., Hoogenboezem, R. M., Samsom, J. N., & Cupedo, T. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.11.115 · Cited by 58 · see citing works
BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice
Hayakawa, Y., Tsuboi, M., Asfaha, S., Kinoshita, H., Niikura, R., Konishi, M., Hata, M., Oya, Y., Kim, W., Middelhoff, M. A., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.11.024 · Cited by 55 · see citing works
Host-microbiota interaction in intestinal stem cell homeostasis
Wu, H., Mu, C., Xu, L., Yu, K., Shen, L., & Zhu, W. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2353399 · Cited by 57 · see citing works
Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways
Kikuchi, I., Takahashi‐Kanemitsu, A., Sakiyama, N., Tang, C., Tang, P.-J., Noda, S., Nakao, K., Kassai, H., Sato, T., Aiba, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms12887 · Cited by 54 · see citing works
Huan, Y. W., Bengtsson, R. J., MacIntyre, N. R., Guthrie, J., Finlayson, H. A., Smith, S. H., Archibald, A. L., & Aït-Ali, T. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173782 · Cited by 54 · see citing works
Liang, S., Li, X., & Wang, X. (2019) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x14666190429143734 · Cited by 54 · see citing works
LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate
Gao, Y., Yan, Y., Tripathi, S., Pentinmikko, N., Amaral, A. I., Päivinen, P., Domènech‐Moreno, E., Andersson, S., Wong, I. P. L., Clevers, H. C., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.12.033 · Cited by 53 · see citing works
Schumacher, M. A., Hsieh, J. J., Liu, C. Y., Appel, K. L., Waddell, A., Almohazey, D., Katada, K., Bernard, J. K., Bucar, E. B., Gadeock, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21113-7 · Cited by 51 · see citing works
Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types
Mead, B. E., Ordovás-Montañés, J., Braun, A. P., Levy, L. E., Bhargava, P., Szucs, M. J., Ammendolia, D. A., MacMullan, M. A., Yin, X., Hughes, T. K., et al. (2018) · BMC Biology · doi:10.1186/s12915-018-0527-2 · Cited by 48 · see citing works
Transcriptomic and proteomic signatures of stemness and differentiation in the colon crypt
Habowski, A. N., Flesher, J. L., Bates, J. M., Tsai, C., Martin, K., Zhao, R., Ganesan, A. K., Edwards, R. A., Shi, T., Wiley, H. S., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01181-z · Cited by 47 · see citing works
Lee, S., Remark, L. H., Josephson, A. M., Leclerc, K., Muiños-López, E., Kirby, D. J., Mehta, D. D., Litwa, H. P., Wong, M. Z., Shin, S. Y., et al. (2021) · npj Regenerative Medicine · doi:10.1038/s41536-021-00139-x · Cited by 51 · see citing works
ARTS mediates apoptosis and regeneration of the intestinal stem cell niche
Koren, E., Yosefzon, Y., Ankawa, R., Soteriou, D., Jacob, A., Nevelsky, A., Ben-Yosef, R., Bar‐Sela, G., & Fuchs, Y. (2018) · Nature Communications · doi:10.1038/s41467-018-06941-4 · Cited by 47 · see citing works
Sphyris, N., Hodder, M. C., & Sansom, O. J. (2021) · Cancers · doi:10.3390/cancers13051000 · Cited by 45 · see citing works
Zhang, Z., Zhang, F., Davis, A. K., Xin, M., Walz, G., Tian, W., & Zheng, Y. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110009 · Cited by 46 · see citing works
Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis
Dempsey, P. J. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.07.011 · Cited by 44 · see citing works
Kim, C.-K., Saxena, M., Maharjan, K., Song, J. J., Shroyer, K. R., Bialkowska, A. B., Shivdasani, R. A., & Yang, V. W. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.11.009 · Cited by 43 · see citing works
Bioengineered Scaffolds for Stem Cell Applications in Tissue Engineering and Regenerative Medicine
Rahmati, M., Pennisi, C. P., Mobasheri, A., & Mozafari, M. (2018) · Advances in experimental medicine and biology · doi:10.1007/5584_2018_215 · Cited by 42 · see citing works
Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models
Mieszczanek, J., van Tienen, L. M., Ibrahim, A. E. K., Winton, D. J., & Bienz, M. (2019) · Nature Communications · doi:10.1038/s41467-018-08164-z · Cited by 42 · see citing works
Large intestine embryogenesis: Molecular pathways and related disorders (Review)
Kostouros, A., Koliarakis, I., Natsis, K. S., Spandidos, D. A., Tsatsakis, A. M., & Tsiaoussis, J. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4583 · Cited by 44 · see citing works
RHOA GTPase Controls YAP-Mediated EREG Signaling in Small Intestinal Stem Cell Maintenance
Liu, M., Zhang, Z., Sampson, L. L., Zhou, X., Nalapareddy, K., Feng, Y., Akunuru, S., Meléndez, J., Davis, A. K., Bi, F., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.004 · Cited by 40 · see citing works
Cellular Composition and Differentiation Signaling in Chicken Small Intestinal Epithelium
Zhang, H., Li, D., Liu, L., Xu, L., Zhu, M., He, X., & Liu, Y. (2019) · Animals · doi:10.3390/ani9110870 · Cited by 40 · see citing works
Forsyth, C. B., Shaikh, M. W., Bishehsari, F., Swanson, G. R., Voigt, R. M., Dodiya, H. B., Wilkinson, P. A., Samelco, B., Song, S., & Keshavarzian, A. (2017) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13519 · Cited by 39 · see citing works
Epigenetic regulation of the intestinal epithelium
Elliott, E. N., & Kaestner, K. H. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1997-9 · Cited by 38 · see citing works
Maintenance of high-turnover tissues during and beyond homeostasis
Banjac, I., Maimets, M., & Jensen, K. B. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.008 · Cited by 37 · see citing works
Linking stem cell function and growth pattern of intestinal organoids
Thalheim, T., Quaas, M., Herberg, M., Braumann, U., Kerner, C., Loeffler, M., Aust, G., & Galle, J. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.10.013 · Cited by 37 · see citing works
miR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Goga, A., Yağabasan, B., Herrmanns, K., Godbersen, S., Silva, P. N., Denzler, R., Zünd, M., Furter, M., Schwank, G., Sunagawa, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23298-3 · Cited by 37 · see citing works
Smith, N. R., Davies, P. S., Levin, T. G., Gallagher, A. C., Keene, D. R., Sengupta, S. K., Wieghard, N., Rassi, E. T. E., & Wong, M. H. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.12.010 · Cited by 36 · see citing works
A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells
Siegle, L., Schwab, J. D., Werle, S. D., Lausser, L. M., Tümpel, S., Pfister, A. S., Kühl, M., & Kestler, H. A. (2018) · PLoS ONE · doi:10.1371/journal.pone.0195126 · Cited by 36 · see citing works
Bigas, A., & Porcheri, C. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-89512-3_12 · Cited by 36 · see citing works
Rapid Crypt Cell Remodeling Regenerates the Intestinal Stem Cell Niche after Notch Inhibition
Bohin, N., Keeley, T. M., Carulli, A. J., Walker, E. M., Carlson, E. A., Gao, J., Aifantis, I., Siebel, C. W., Rajala, M. W., Myers, M. G., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.05.010 · Cited by 37 · see citing works
Self-citationSuspension culture promotes serosal mesothelial development in human intestinal organoids
Capeling, M. M., Huang, S., Childs, C. J., Wu, J. H., Tsai, Y.-H., Wu, A., Garg, N., Holloway, E. M., Sundaram, N., Bouffi, C., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110379 · Cited by 36 · see citing works
Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
Goto, N., Ueo, T., Fukuda, A., Kawada, K., Sakai, Y., Miyoshi, H., Taketo, M. M., Chiba, T., & Seno, H. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3192 · Cited by 33 · see citing works
Bao, W., You, Y., Ni, J., Hou, H., Lyu, J., Feng, G., Wang, Y., You, K., Zhang, S., Zhang, L., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh5016 · Cited by 34 · see citing works
Time after time: circadian clock regulation of intestinal stem cells
Parasram, K., & Karpowicz, P. A. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03323-x · Cited by 34 · see citing works
Overview of Basic Mechanisms of Notch Signaling in Development and Disease
McIntyre, B. A. S., Asahara, T., & Alev, C. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-36422-9_2 · Cited by 34 · see citing works
Saqui–Salces, M., Huang, Z., Vila, M. F., Li, J., Mielke, J. A., Urriola, P. E., & Shurson, G. C. (2017) · Journal of Animal Science · doi:10.2527/jas.2016.0947 · Cited by 33 · see citing works
Reyes, E. A., Castillo‐Azofeifa, D., Rispal, J., Wald, T., Zwick, R. K., Palikuqi, B., Mujukian, A., Rabizadeh, S., Gupta, A. R., Gardner, J. M., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci163591 · Cited by 31 · see citing works
Self-citationTuft cells in the intestine, immunity and beyond
Feng, X., Flüchter, P., de Tenorio, J. C., & Schneider, C. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00978-1 · Cited by 30 · see citing works
Activation of endothelial β-catenin signaling induces heart failure
Nakagawa, A., Naito, A. T., Sumida, T. S., Nomura, S., Shibamoto, M., Higo, T., Okada, K., Sakai, T., Hashimoto, A., Kuramoto, Y., et al. (2016) · Scientific Reports · doi:10.1038/srep25009 · Cited by 30 · see citing works
Angius, A., Scanu, A. M., Arru, C., Muroni, M. R., Rallo, V., Deiana, G., Ninniri, C., Carru, C., Porcu, A., Pira, G., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041603 · Cited by 30 · see citing works
Hansen, S., Zhang, Y., Hwang, S., Nabhan, A. N., Li, W., Fuhrmann, J., Kschonsak, Y. T., Zhou, L., Nile, A. H., Gao, X., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207327119 · Cited by 30 · see citing works
Hogstrom, J. M., Heino, S., Kallio, P., Lähde, M., Leppänen, V., Balboa, D., Wiener, Z., & Alitalo, K. K. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0451 · Cited by 30 · see citing works
Das, D., Fletcher, R. B., & Ngai, J. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.361 · Cited by 29 · see citing works
TNIK signaling imprints CD8+ T cell memory formation early after priming
Jaeger-Ruckstuhl, C. A., Hinterbrandner, M., Höpner, S., Correnti, C., Lüthi, U., Friedli, O., Freigang, S., Sayed, M. F. A., Bührer, E. D., Amrein, M. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15413-7 · Cited by 26 · see citing works
Zhang, H., Pertiwi, H., Hou, Y., Majdeddin, M., & Michiels, J. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.170410 · Cited by 26 · see citing works
The Hippo Pathway Effector YAP1 Regulates Intestinal Epithelial Cell Differentiation
Fallah, S., & Beaulieu, J. (2020) · Cells · doi:10.3390/cells9081895 · Cited by 25 · see citing works
Kong, X., Wang, X., Qin, Y., & Han, J. (2020) · Journal of Applied Toxicology · doi:10.1002/jat.4080 · Cited by 25 · see citing works
- Authors
- Tian, H., Biehs, B., Chiu, C., Siebel, C. W., Wu, Y., Costa, M., de Sauvage, F. J., & Klein, O. D.
- Affiliations
- University of California, San Francisco (US)
- Genentech (US)
- Corresponding author
- Klein, Ophir D.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 11
- Issue
- 1
- Pages
- 33-42
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4394041
- OpenAlex
- W2081080915
- Cited by
- 214
- References
- 27
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 16 · 2023: 19 · 2022: 17 · 2021: 20 · 2020: 29 · 2019: 15 · 2018: 27 · 2017: 21 · 2016: 14 · 2015: 6 · 2012: 1
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (1dp2od007191-01)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK085532, U01DK103147, U01DK085532)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- Notch signaling, Wnt signaling, intestinal stem cells, intestinal homeostasis, small intestine, secretory cell differentiation, stem cell maintenance, adult stem cells
- MeSH terms
- Animals, Cell Differentiation, Gene Expression Regulation, Homeostasis, Intestinal Mucosa, Stem Cells, Cell Lineage, Cell Proliferation, Mice, Receptors, Notch, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
