Lgr5 stem cells are indispensable for radiation-induced intestinal regeneration
Open accessAbstract
The intestinal epithelium continually self-renews and can rapidly regenerate after damage. Lgr5 marks mitotically active intestinal stem cells (ISCs). Importantly, intestinal homeostasis can be maintained after depletion of Lgr5(+) cells due to the activation of Lgr5(-) reserve ISCs. The Lgr5(-) ISC populations are thought to play a similar role during intestinal regeneration following radiation-induced damage. We tested this regeneration hypothesis by combining depletion of Lgr5(+) ISCs with radiation exposure. In contrast to the negligible effect of Lgr5(+) ISC loss during homeostasis, depletion of Lgr5(+) cells during radiation-induced damage and subsequent repair caused catastrophic crypt loss and deterioration of crypt-villus architecture. Interestingly though, we found that crypts deficient for Lgr5(+) cells are competent to undergo hyperplasia upon loss of Apc. These data argue that Lgr5(-) reserve stem cells are radiosensitive and that Lgr5(+) cells are crucial for robust intestinal regeneration following radiation exposure but are dispensable for premalignant hyperproliferation.
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Irradiation in the intestinal epithelium is accompanied by crypt shrinking because of apoptosis, followed by a burst of proliferative response predominantly from existing/surviving ISCs.
“Irradiation in the intestinal epithelium is accompanied by crypt shrinking because of apoptosis, followed by a burst of proliferative response predominantly from existing/surviving ISCs (Metcalfe et al., 2014), usually leading to an increase in crypt depth followed by crypt fission.”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Metcalfe et al., 2014
Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
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
Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y., & NAKAYA, R. (1990) · Gastroenterology · doi:10.1016/0016-5085(90)90290-h · Cited by 2,405 · see citing works
Crypt stem cells as the cells-of-origin of intestinal cancer
Barker, N., Ridgway, R. A., van Es, J. H., van de Wetering, M., Begthel, H., van den Born, M., Danenberg, E., Clarke, A. R., Sansom, O. J., & Clevers, H. C. (2008) · Nature · doi:10.1038/nature07602 · Cited by 2,159 · see citing works
Stem cells, self-renewal, and differentiation in the intestinal epithelium.
van der Flier, L. G., & Clevers, H. (2009) · Annual Review of Physiology · doi:10.1146/annurev.physiol.010908.163145 · Cited by 1,859 · see citing works
Cheng, H., & Leblond, C. P. (1974) · American Journal of Anatomy · doi:10.1002/aja.1001410407 · Cited by 1,737 · see citing works
A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable
Tian, H., Biehs, B., Warming, S., Leong, K. G., Rangell, L. K., Klein, O. D., & de Sauvage, F. J. (2011) · Nature · doi:10.1038/nature10408 · Cited by 1,194 · see citing works
Bmi1 is expressed in vivo in intestinal stem cells
Sangiorgi, E., & Capecchi, M. R. (2008) · Nature Genetics · doi:10.1038/ng.165 · Cited by 1,192 · see citing works
The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations
Yan, K. S., Chia, L. A., Li, X., Ootani, A., Su, J., Lee, J. Y., Su, N. Y., Luo, Y., Heilshorn, S. C., Amieva, M. R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1118857109 · Cited by 817 · see citing works
Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migrationPreprint
Sansom, O. J., Reed, K. R., Hayes, A. J., Ireland, H., Brinkmann, H., Newton, I. P., Batlle, E., Simon-Assmann, P. M., Clevers, H. C., Näthke, I. S., et al. (2004) · Genes & Development · doi:10.1101/gad.287404 · Cited by 799 · see citing works
Dll1+ secretory progenitor cells revert to stem cells upon crypt damage
van Es, J. H., Sato, T., van de Wetering, M., Lyubimova, A., Nee, A. N. Y., Gregorieff, A., Sasaki, N., Zeinstra, L. M., van den Born, M., Korving, J., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2581 · Cited by 781 · 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
The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers
Muñoz, J., Stange, D. E., Schepers, A. G., van de Wetering, M., Koo, B., Itzkovitz, S., Volckmann, R., Kung, K. S., Köster, J., Radulescu, S., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.166 · Cited by 758 · see citing works
mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake
Yilmaz, Ö. H., Katajisto, P., Lamming, D. W., Gültekin, Y., Bauer-Rowe, K. E., Sengupta, S., Birsoy, K., Dursun, A., Yilmaz, V. O., Selig, M., et al. (2012) · Nature · doi:10.1038/nature11163 · Cited by 753 · see citing works
Interconversion Between Intestinal Stem Cell Populations in Distinct Niches
Takeda, N., Jain, R., LeBoeuf, M. R., Wang, Q., Lu, M. M., & Epstein, J. A. (2011) · Science · doi:10.1126/science.1213214 · Cited by 742 · see citing works
Microcolony Survival Assay for Cells of Mouse Intestinal Mucosa Exposed to Radiation
Withers, H. R., & Elkind, M. M. (1970) · International Journal of Radiation Biology and Related Studies in Physics Chemistry and Medicine · doi:10.1080/09553007014550291 · Cited by 707 · see citing works
Powell, A. E., Wang, Y., Li, Y., Poulin, E. J., Means, A. L., Washington, M. K., Higginbotham, J. N., Juchheim, A., Prasad, N., Levy, S. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.042 · Cited by 694 · see citing works
The intestinal epithelial stem cell
Marshman, E., Booth, C., & Potten, C. S. (2002) · BioEssays · doi:10.1002/bies.10028 · Cited by 588 · see citing works
Mitogenic Influence of Human R-Spondin1 on the Intestinal Epithelium
Kim, K., Kakitani, M., Zhao, J., Oshima, T., Tang, T., Binnerts, M. E., Liu, Y., Boyle, B., Park, E., Emtage, P. C. R., et al. (2005) · Science · doi:10.1126/science.1112521 · Cited by 587 · see citing works
Merritt, A. J., Potten, C. S., Kemp, C. J., Hickman, J. A., Balmain, A., Lane, D. P., & Hall, P. A. (1994) · PubMed · Cited by 560 · see citing works
Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells
Montgomery, R. K., Carlone, D. L., Richmond, C. A., Farilla, L., Kranendonk, M. E. G., Henderson, D. E., Baffour‐Awuah, N. Y., Ambruzs, D. M., Fogli, L. K., Algra, S. O., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013004108 · Cited by 537 · see citing works
The intestinal epithelial stem cell: the mucosal governor
Potten, C. S., Booth, C., & Pritchard, D. M. (1997) · International Journal of Experimental Pathology · doi:10.1046/j.1365-2613.1997.280362.x · Cited by 490 · see citing works
Extreme sensitivity of some intestinal crypt cells to X and γ irradiation
Potten, C. S. (1977) · Nature · doi:10.1038/269518a0 · Cited by 441 · see citing works
DNA-Damage Response in Tissue-Specific and Cancer Stem Cells
Blanpain, C., Mohrin, M., Sotiropoulou, P. A., & Passegue, E. A. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.012 · Cited by 350 · see citing works
Durand, A., Donahue, B., Peignon, G., Letourneur, F., Cagnard, N., Slomianny, C., Perret, C., Shroyer, N. F., & Romagnolo, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201652109 · Cited by 322 · see citing works
Identifying the Stem Cell of the Intestinal Crypt: Strategies and Pitfalls
Barker, N., van Oudenaarden, A., & Clevers, H. C. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.09.009 · Cited by 320 · see citing works
Potten, C. S. (2004) · Radiation Research · doi:10.1667/rr3104 · Cited by 212 · see citing works
Crypt Base Columnar Stem Cells in Small Intestines of Mice Are Radioresistant
Hua, G., Thin, T. H., Feldman, R., Haimovitz‐Friedman, A., Clevers, H. C., FUKS, Z. Y., & Kolesnick, R. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.07.106 · Cited by 206 · see citing works
Ashton, G. H. S., Morton, J. P., Myant, K., Phesse, T. J., Ridgway, R. A., Marsh, V. L., Wilkins, J. A., Athineos, D., Muncan, V., Kemp, R., et al. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.07.015 · Cited by 189 · see citing works
Adenomatous Polyposis Coli (APC) Is Required for Normal Development of Skin and Thymus
Kuraguchi, M., Wang, X.-P., Bronson, R. T., Rothenberg, R., Baah, N. O., Lund, J. J., Kucherlapati, M. H., Maas, R. L., & Kucherlapati, R. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020146 · Cited by 186 · see citing works
The stem cells of small intestinal crypts: where are they?
Potten, C. S., Gândara, R., Mahida, Y., Loeffler, M., & Wright, N. A. (2009) · Cell Proliferation · doi:10.1111/j.1365-2184.2009.00642.x · Cited by 184 · see citing works
Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection
Zhou, W., Geng, Z. H., Spence, J. R., & Geng, J.-G. (2013) · Nature · doi:10.1038/nature12416 · Cited by 155 · 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
Bhanja, P., Saha, S., Kabarriti, R., Liu, L., Roy‐Chowdhury, N., Roy‐Chowdhury, J., Sellers, R. S., Alfieri, A. A., & Guha, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008014 · Cited by 128 · see citing works
Yücel, R., Kosan, C., Heyd, F., & Möröy, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400808200 · Cited by 122 · see citing works
Fafílek, B., Krausová, M., Vojtěchová, M., Pospíchalová, V., Tůmová, L., Šloncová, E., Huranová, M., Stančíková, J., Hlavatá, A., Švec, J., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.10.048 · Cited by 108 · see citing works
Apoptosis Differently Affects Lineage Tracing of Lgr5 and Bmi1 Intestinal Stem Cell Populations
Zhu, Y., Huang, Y., Kek, C., & Bulavin, D. V. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.01.003 · Cited by 88 · see citing works
Hirata, A., Utikal, J. S., Yamashita, S., Aoki, H., Watanabe, A., Yamamoto, T., Okano, H., Bardeesy, N. M., Kunisada, T., Ushijima, T., et al. (2012) · Development · doi:10.1242/dev.084103 · Cited by 70 · see citing works
Wnt signalling and its role in stem cell‐driven intestinal regeneration and hyperplasia
Cordero, J. B., & Sansom, O. J. (2011) · Acta Physiologica · doi:10.1111/j.1748-1716.2011.02288.x · Cited by 53 · see citing works
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- Authors
- Metcalfe, C., Kljavin, N. M., Ybarra, R., & de Sauvage, F. J.
- Affiliations
- Genentech (US)
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 14
- Issue
- 2
- Pages
- 149-159
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2029556699
- Cited by
- 575
- References
- 40
- Citations by year
- 2026: 39 · 2025: 36 · 2024: 48 · 2023: 36 · 2022: 46 · 2021: 52 · 2020: 59 · 2019: 50 · 2018: 61 · 2017: 42 · 2016: 41 · 2015: 41 · 2014: 24
- FWCI
- 18.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Lgr5, intestinal stem cells, radiation enteritis, intestinal regeneration, APC loss, intestinal hyperplasia, stem cell depletion, intestinal homeostasis
- MeSH terms
- Animals, Colitis, Diphtheria Toxin, Dose-Response Relationship, Radiation, Hyperplasia, Intestines, Radiation, Ionizing, Regeneration, Stem Cells, Dextran Sulfate, Paneth Cells, Models, Animal, Adenomatous Polyposis Coli Protein, Receptors, G-Protein-Coupled, Mice
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