Epithelial WNT ligands are essential drivers of intestinal stem cell activation
Open accessAbstract
Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior.
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Murine muscle stem cells (MuSCs) experience a transition from quiescence to activation that is required for regeneration.
“Murine muscle stem cells (MuSCs) experience a transition from quiescence to activation that is required for regeneration, but it remains unknown if the trajectory and dynamics of activation change with age.”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Zou et al., 2018
Impaired stem cell activation impairs regenerative potential in multiple tissues.
“Impaired stem cell activation has been shown to impair regenerative potential in multiple tissues (Megeney et al., 1996; Zou et al., 2018).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Zou et al., 2018
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The Intestinal Stem Cell Niche: Homeostasis and Adaptations
Santos, A. J. M., Lo, Y., Mah, A. T., & Kuo, C. J. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.08.001 · Cited by 277 · see citing works
Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium
Pentinmikko, N., Iqbal, S., Mana, M., Andersson, S., Cognetta, A. B., Suciu, R. M., Roper, J., Luopajärvi, K., Markelin, E., Gopalakrishnan, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1383-0 · Cited by 271 · see citing works
Brock, C. K., Wallin, S. T., Ruiz, O. E., Samms, K. M., Mandal, A., Sumner, E. A., & Eisenhoffer, G. T. (2019) · Nature Communications · doi:10.1038/s41467-019-09010-6 · Cited by 185 · see citing works
Cellular Plasticity in Intestinal Homeostasis and Disease
Melo, F. D. S. E., & de Sauvage, F. J. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.11.019 · Cited by 175 · see citing works
Yu, M. S., Qin, K. H., Fan, J., Zhao, G., Zhao, P., Zeng, W., Chen, C., Wang, A., Wang, Y., Zhong, J., et al. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.04.042 · Cited by 118 · see citing works
Aging induces aberrant state transition kinetics in murine muscle stem cells
Kimmel, J. C., Hwang, A. B., Scaramozza, A., Marshall, W. F., & Brack, A. S. (2020) · Development · doi:10.1242/dev.183855 · Cited by 95 · see citing works
Li, B., Lee, C. M., Cadete, M., Zhu, H., Koike, Y., Hock, A., Wu, R., Botts, S. R., Minich, A., Alganabi, M., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1987-1 · Cited by 95 · see citing works
Kang, E. S., Kim, J., Kim, Y. E., Lee, H., Jung, K. B., Chang, D., Lee, Y., Park, S., Lee, E., Lee, E.-J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47275-8 · Cited by 94 · see citing works
Li, N., Lü, N., & Xie, C. (2019) · FEBS Journal · doi:10.1111/febs.15017 · Cited by 96 · see citing works
Macrophages as an Emerging Source of Wnt Ligands: Relevance in Mucosal Integrity
Cosín‐Roger, J., Ortiz‐Masiá, D., & Barrachina, M. D. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02297 · Cited by 80 · see citing works
Bomidi, C., Robertson, M. J., Coarfa, C., Estes, M. K., & Blutt, S. E. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112814118 · Cited by 65 · see citing works
Zhou, J., Huang, D., Zhu, M., Gao, C., Yan, H., Li, X., & Wang, X. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29492 · Cited by 64 · see citing works
Johansson, J., Nászai, M., Hodder, M. C., Pickering, K. A., Miller, B. W., Ridgway, R. A., Yu, Y., Peschard, P., Brachmann, S. M., Campbell, A. D., et al. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.02.002 · Cited by 54 · see citing works
IL-22–induced cell extrusion and IL-18–induced cell death prevent and cure rotavirus infection
Zhang, Z., Zou, J., Shi, Z., Zhang, B., Etienne‐Mesmin, L., Wang, Y., Shi, X., Shao, F., Chassaing, B., & Gewirtz, A. T. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd2876 · Cited by 49 · see citing works
Sphyris, N., Hodder, M. C., & Sansom, O. J. (2021) · Cancers · doi:10.3390/cancers13051000 · Cited by 45 · see citing works
Intestinal renewal across the animal kingdom: comparing stem cell activity in mouse and Drosophila
Zwick, R. K., Ohlstein, B., & Klein, O. D. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00353.2018 · Cited by 42 · see citing works
Investigating local and systemic intestinal signalling in health and disease with Drosophila
Medina, A. B., Bellec, K., Polcowñuk, S., & Cordero, J. B. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049332 · Cited by 36 · see citing works
Stromal control of intestinal development and the stem cell niche
Greicius, G., & Virshup, D. M. (2019) · Differentiation · doi:10.1016/j.diff.2019.01.001 · Cited by 38 · see citing works
REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration
Zhu, X., Yang, M., Lin, Z., Kibreab, S., Li, Y., Zhang, L., Kong, Y., Zhang, Y., Ren, Y., Li, J., et al. (2021) · Science China Life Sciences · doi:10.1007/s11427-021-2018-7 · Cited by 34 · see citing works
Defence and adaptation mechanisms of the intestinal epithelium upon infection
Iftekhar, A., & Sigal, M. J. (2021) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2021.151486 · Cited by 33 · see citing works
CREPT is required for murine stem cell maintenance during intestinal regeneration
Liu, Y., Yang, H., Chu, Y., Song, Y., Ding, L., Zhu, B., Zhai, W., Wang, X., Kuang, Y., Ren, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20636-9 · Cited by 32 · see citing works
Microbial recognition regulates intestinal epithelial growth in homeostasis and disease
Ferguson, M., & Foley, E. (2021) · FEBS Journal · doi:10.1111/febs.15910 · Cited by 28 · see citing works
Use of organoids to study regenerative responses to intestinal damage
Blutt, S. E., Klein, O. D., Donowitz, M., Shroyer, N. F., Guha, C., & Estes, M. K. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00346.2018 · Cited by 27 · see citing works
Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche
Quintero, M. K., & Samuelson, L. C. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.101443 · Cited by 26 · see citing works
Bhat, V. S., Cohen, S. M., Gordon, E. B., Wood, C. E., Cullen, J. M., Harris, M. A., Proctor, D. M., & Thompson, C. M. (2020) · Critical Reviews in Toxicology · doi:10.1080/10408444.2020.1823934 · Cited by 26 · see citing works
Tian, J., Li, Y., Bao, X., Yang, F., Tang, X., Jiang, Q., Yang, C., Yin, Y., & Kang, Y. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.05.012 · Cited by 23 · see citing works
Lamisere, H., Bhalchandra, S., Kane, A. V., Zeng, X., Mo, D., Adams, W., Estes, M. K., & Ward, H. (2022) · Infection and Immunity · doi:10.1128/iai.00397-22 · Cited by 22 · see citing works
The intestinal epithelial response to damage
Weichselbaum, L., & Klein, O. D. (2018) · Science China Life Sciences · doi:10.1007/s11427-018-9331-y · Cited by 22 · see citing works
Castillo‐Azofeifa, D., Wald, T., Reyes, E. A., Gallagher, A. P., Schanin, J., Vlachos, S., Lamarche‐Vane, N., Bomidi, C., Blutt, S. E., Estes, M. K., et al. (2023) · Cell stem cell · doi:10.1016/j.stem.2022.12.008 · Cited by 21 · see citing works
Perez, A. C., Santos-de-Frutos, K., de la Rosa, S., Herranz-Montoya, I., Perna, C., & Djouder, N. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212405 · Cited by 17 · see citing works
Kaiser, K. N., Snyder, J. R., Koppes, R. A., & Koppes, A. N. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202409718 · Cited by 17 · see citing works
Replicates in stem cell models—How complicated!
Chan, J. C. W., & Teo, A. K. K. (2020) · Stem Cells · doi:10.1002/stem.3237 · Cited by 16 · see citing works
Targeting STAT3 and STAT5 in Cancer
de Araujo, E. D., Keserű, G. M., Gunning, P. T., & Moriggl, R. (2020) · Cancers · doi:10.3390/cancers12082002 · Cited by 17 · see citing works
In, J., Yin, J., Atanga, R., Doucet, M., Cole, R. N., Devine, L. R., Donowitz, M., Zachos, N. C., Blutt, S. E., Estes, M. K., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101618 · Cited by 17 · see citing works
Modulation of stem cell fate in intestinal homeostasis, injury and repair
Wang, Z., Qu, Y.-J., & Cui, M. (2023) · World Journal of Stem Cells · doi:10.4252/wjsc.v15.i5.354 · Cited by 18 · see citing works
Fang, Y.-X., Lu, E.-Q., Cheng, Y.-J., Xu, E., Zhu, M., & Chen, X. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c08701 · Cited by 16 · see citing works
Colonic healing requires Wnt produced by epithelium as well as Tagln+ and Acta2+ stromal cells
Das, S., Feng, Q., Balasubramanian, I., Lin, X., Liu, H., Pellón-Cárdenas, O., Yu, S., Zhang, X., Liu, Y., Wei, Z., et al. (2021) · Development · doi:10.1242/dev.199587 · Cited by 14 · see citing works
Poplaski, V. B., Bomidi, C., Kambal, A., Nguyen‐Phuc, H., Rienzi, S. C. D., Danhof, H. A., Zeng, X.-L., Feagins, L. A., Deng, N., Vilar, E., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci166884 · Cited by 15 · see citing works
Ayansola, H., Mayorga, E. J., & Jin, Y. (2024) · Biomedicines · doi:10.3390/biomedicines12030668 · Cited by 12 · see citing works
Othman, S. B., Ido, K., Masuda, R., Gotoh, S., Hosoda‐Yabe, R., Kitaguchi, K., & Yabe, T. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111099 · Cited by 12 · see citing works
Zymosan-A promotes the regeneration of intestinal stem cells by upregulating ASCL2
Du, J., Lan, F., Zhao, J., Yu, Y., Feng, Z., Wang, Y., Cheng, Y. H., Li, B., Gao, F., & Liu, C. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05301-x · Cited by 11 · see citing works
Zan, G.-X., Wang, X., Yan, S.-K., Qin, Y., Yao, L.-Q., Gao, C., Yan, H., Zhou, J., & Wang, X. (2024) · Phytomedicine · doi:10.1016/j.phymed.2024.155363 · Cited by 11 · see citing works
Tian, J., Li, Y., Bao, X., Yang, F., Tang, X., Jiang, Q., Yin, Y., & Kang, Y. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03293-9 · Cited by 10 · see citing works
Zhou, J., Xie, W.-W., Hu, T.-C., Wang, X., Yan, H., & Wang, X. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c09909 · Cited by 10 · see citing works
Taking a Step Back: Insights into the Mechanisms Regulating Gut Epithelial Dedifferentiation
Ouladan, S., & Gregorieff, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137043 · Cited by 9 · see citing works
Peyer’s Patch B Cells Sample Transglutaminase-Gluten Complexes and Drive Celiac Disease Autoimmunity
du Pré, M. F., Kleppa, L., Dewan, A. E., Meling, M. T., Høydahl, L. S., Besser, H. A., Khosla, C., & Sollid, L. M. (2025) · Gastroenterology · doi:10.1053/j.gastro.2025.06.021 · Cited by 9 · see citing works
Yang, J., & Shi, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1184159 · Cited by 7 · see citing works
Chen, N., Feng, Q., Deng, J., Xiong, Y., Deng, Y.-J., Wang, M., Zhou, L., Yu, Q., Hu, J., & Deng, H. (2020) · PubMed Central · Cited by 7 · see citing works
Qu, F., Li, D., Zhang, S., Zhang, C., & Shen, A. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.116396 · Cited by 6 · see citing works
Vemuri, K., Kumar, S., Chen, L., & Verzi, M. P. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114242 · Cited by 5 · see citing works
Wang, Z., Li, P., Li, C.-N., Guo, Y.-N., Shao, Y.-Z., Yan, Q., Wen, L., Wang, Y., & Hu, F. (2024) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2024.100391 · Cited by 5 · see citing works
Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation
Rannikmäe, H., Peel, S. E., Barry, S. T., Sur, I., Taipale, J., Senda, T., & de la Roche, M. (2021) · Journal of Cell Science · doi:10.1242/jcs.250019 · Cited by 5 · see citing works
Bose, A., & Visweswariah, S. S. (2025) · Biochemical Journal · doi:10.1042/bcj20253055 · Cited by 5 · see citing works
Wong, M. K., Uchida, M., & Tsukada, T. (2020) · Cell and Tissue Research · doi:10.1007/s00441-019-03140-5 · Cited by 4 · see citing works
Drug Class Review: Skeletal Muscle Relaxants: Final Report
Chou, R., & Peterson, K. J. (2005) · Cited by 4 · see citing works
Kim, J. M., Yoo, K.-C., Kim, J., Lee, S. B., Son, Y., Lee, H., Choi, S.-P., Kim, H. B., Lee, S., Cho, S. S., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118879 · Cited by 3 · see citing works
Loss of mucin 2 and MHC II molecules causes rare resistance to murine RV infection
Bomidi, C., Sawyer, F. M., Shroyer, N. F., Conner, M. E., Estes, M. K., & Blutt, S. E. (2024) · Journal of Virology · doi:10.1128/jvi.01507-24 · Cited by 3 · see citing works
Qu, H., Zan, G.-X., Li, H., Wang, X., Zhou, J., Wang, X., & Yan, H. (2025) · Fermentation · doi:10.3390/fermentation11020052 · Cited by 3 · see citing works
Decoding mechanisms of diarrhea induction by enteric viruses
Hou, G., & Ding, S. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012414 · Cited by 3 · see citing works
Gfi1-expressing Paneth cells revert to stem cells following intestinal injuryPreprint
Chen, M., Lo, Y., Butkus, J. M., Zou, W. Y., Tseng, Y.-J., Jen, H., Patel, S., Groves, A. K., Estes, M. K., Sahin, E., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/364133 · Cited by 3 · see citing works
Bu, X.-Y., Tan, H., Wang, A. M., Wei, M.-T., Pan, S., Gao, J.-Z., Li, Y., Qian, G., Chen, Z., Ye, C., et al. (2025) · World Journal of Gastroenterology · doi:10.3748/wjg.v31.i26.107044 · Cited by 2 · see citing works
Alcohol Preference Impacts Multi-Organ Transcriptome in MetALD
Sikhwal, S., Gripshover, T. C., Treves, R. S., & Hardesty, J. (2025) · Genes · doi:10.3390/genes16101121 · Cited by 2 · see citing works
IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infectionPreprint
Zhang, Z., Zou, J., Shi, Z., Zhang, B., Etienne‐Mesmin, L., Chassaing, B., & Gewirtz, A. T. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/774984 · Cited by 2 · see citing works
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Mechanistic insights into intestinal stem cell disruption during infection
Chege, N., & Finney, C. A. M. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00352.2024 · Cited by 3 · see citing works
IPSC-derived intestinal organoids and current 3D intestinal scaffolds
Malijauskaite, S., Mulvihill, J. J., Grabrucker, A. M., & McGourty, K. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823809-7.00011-6 · Cited by 1 · see citing works
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Building and regenerating intestines by manipulating intestinal stem cells
Kuo, C. J., Blutt, S. E., Donowitz, M., Estes, M. K., Guha, C., Klein, O. D., Li, L., Niland, J. C., Santos, A. J. M., Shivdasani, R. A., et al. (2026) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-026-01242-4
Paneth cell-derived Notch ligands DLL1 and DLL4 are crucial for intestinal crypt base stem cellsPreprint
Quintero, M. K., Keeley, T. M., Colacino, J. A., Gao, N., Dempsey, P. J., & Samuelson, L. C. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.14.751473
Dawson, Z. D., Martin, T., Ji, E., Lee, K. E., Chen, X., Zhou, X., Jean, S. S., Li, Y., & Ma, J. (2026) · Biomolecules · doi:10.3390/biom16101415
- Authors
- Zou, W. Y., Blutt, S. E., Zeng, X.-L., Chen, M.-S., Lo, Y.-H., Castillo-Azofeifa, D., Klein, O. D., Shroyer, N. F., Donowitz, M., & Estes, M. K.
- Affiliations
- Baylor College of Medicine (US)
- University of California, San Francisco (US)
- Johns Hopkins University (US)
- Corresponding author
- Estes, Mary K.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 22
- Issue
- 4
- Pages
- 1003-1015
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5798462
- OpenAlex
- W2784946434
- Cited by
- 73
- References
- 89
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 12 · 2023: 9 · 2022: 4 · 2021: 10 · 2020: 10 · 2019: 11 · 2018: 5
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Dan L. Duncan Cancer Center, Baylor College of Medicine
- John S. Dunn Foundation (CPRIT RP150578)
- National Center for Research Resources (S10RR024574, RP150578, DK56338, CA125123)
- National Cancer Institute (P30CA125123)
- Baylor College of Medicine
- National Institutes of Health (U01 DK103168, U01 DK103168-03S1, F30 DK107173, U01 DK103168-02S1)
- 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 › Genetics › Digestive system and related health
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Keywords
- intestinal stem cells, rotavirus infection, epithelial restitution, Wnt ligands, stem cell activation, epithelial regeneration
- MeSH terms
- Animals, Epithelial Cells, Intestinal Mucosa, Ligands, Stem Cells, Mice
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.
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