Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium
Open accessAbstract
A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche 1,2. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α)3, and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.
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In the intestine, old Paneth cells can secrete increased amounts of NOTUM, which attenuates WNT signalling in ISCs and contributes to stem cell dysfunction and intestinal decline.
“In the intestine, old Paneth cells, which are niche cells, can secrete increased amounts of NOTUM, which in turn attenuates WNT signalling in ISCs and contributes to stem cell dysfunction and intestinal decline132.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [132]
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References 55 · Cited by 271
- Authors
- Pentinmikko, N., Iqbal, S., Mana, M., Andersson, S., Cognetta, A. B., Suciu, R. M., Roper, J., Luopajärvi, K., Markelin, E., Gopalakrishnan, S., Smolander, O.-P., Naranjo, S., Saarinen, T., Juuti, A., Pietiläinen, K., Auvinen, P., Ristimäki, A., Gupta, N., Tammela, T., Jacks, T., Sabatini, D. M., Cravatt, B. F., Yilmaz, Ö. H., & Katajisto, P.
- Affiliations
- University of Helsinki (FI)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Scripps Research Institute (US)
- Duke University (US)
- Helsinki University Hospital (FI)
- Atlanta Gastroenterology Associates (US)
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Katajisto, Pekka
- ORCID
- Venue
- Nature
- Published
- 2019-07-10
- Volume
- 571
- Issue
- 7765
- Pages
- 398-402
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8151802
- OpenAlex
- W2957935821
- Cited by
- 271
- References
- 55
- Citations by year
- 2026: 28 · 2025: 48 · 2024: 42 · 2023: 43 · 2022: 44 · 2021: 30 · 2020: 29 · 2019: 7
- FWCI
- 9.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Helsingin Yliopisto
- European Commission (618774)
- Novo Nordisk Fonden (#NNF10OC1013354, NNF17OC0027232)
- Center for Innovative Medicine
- National Institute on Aging (R00AG045144)
- National Cancer Institute (R01CA034992, P30CA008748, P30CA014051)
- National Institute of General Medical Sciences (T32GM007287)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- notum, Paneth cells, intestinal stem cells, Wnt signaling, stem cell niche, mTORC1, PPARα, intestinal regeneration, intestinal organoids, chemotherapy-induced intestinal damage, tissue regeneration
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Aging, Animals, Esterases, Female, Humans, Intestinal Mucosa, Male, Regeneration, Stem Cells, Cellular Senescence, Paneth Cells, Receptors, G-Protein-Coupled, PPAR alpha, Wnt Proteins, Mice, Stem Cell Niche, Wnt Signaling Pathway
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