Wnt Signaling Mediates the Aging-Induced Differentiation Impairment of Intestinal Stem Cells
Open accessAbstract
Stem cell aging underlies aging-associated disorders, such as steeply increased incidences of tumors and impaired regeneration capacity upon stress. However, whether and how the intestinal stem cells age remains largely unknown. Here we show that intestinal stem cells derived from 24-month-old mice hardly form typical organoids with crypt-villus structures, but rather mainly form big, rounded cysts devoid of differentiated cell types, which mimics the culturing of heterozygous APC-deficient cells from the APC min mouse line. Further analysis showed that cultured crypts derived from aged mice exhibited reduced expression levels of differentiation genes and higher expression of Wnt target genes. Lowering the concentration of R-spondin-1 in the culture system significantly reduced formation of rounded cysts, accompanied by an increased formation of organoids from crypts derived from old mice. We are the first to uncover that intestinal stem cells derived from old mice harbor significant deficiency in differentiation that can be partially rescued through a reduction in R-spondin-1 exposure. This could be highly relevant to intestinal tumor development and the reduced regeneration potential observed in the aged population. Our study provides the first experimental evidence that an over-responsiveness to Wnt/beta-catenin signaling of aged intestinal stem cells mediates the aging-induced deficiency in differentiation, and could serve as a potential target to ameliorate aging-associated intestinal pathologies.
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In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function can lead to increased epithelial barrier permeability.
“In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function [32, 36, 76, 83] can lead to increased epithelial barrier permeability [19, 75, 118, 120]”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [32]
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- Authors
- Cui, H., Tang, D., Garside, G. B., Zeng, T., Wang, Y., Tao, Z., Zhang, L., & Tao, S.
- Affiliations
- Second Affiliated Hospital of Nanchang University (CN)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Peking University (CN)
- Corresponding author
- Tao, Si
- Venue
- Stem Cell Reviews and Reports
- Published
- 2019-02-21
- Volume
- 15
- Issue
- 3
- Pages
- 448-455
- ISSN
- 1550-8943 (ISSN-L)
- 1558-6804
- PMC
- PMC6534527
- OpenAlex
- W2917771007
- Cited by
- 57
- References
- 36
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 11 · 2022: 14 · 2021: 6 · 2020: 8 · 2019: 4
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Stem Cell Reviews and Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- National Natural Science Foundation of China (NSFC-81660520)
- 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 › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- intestinal stem cells, stem cell aging, Wnt/β-catenin signaling, RSPO1, stem cell differentiation, intestinal organoids, ApcMin/+ mice, intestinal regeneration, intestinal tumors
- MeSH terms
- Aging, Animals, Cell Differentiation, Intestinal Mucosa, Intestinal Neoplasms, Mice, Mutant Strains, Stem Cells, Adenomatous Polyposis Coli Protein, Mice, Wnt Signaling Pathway
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