Abstract
To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD+ intermediate. As a result, the organoids showed a higher NAD+ level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.
Highlights
Cells are continuously exposed to aging-associated phenomena such as telomere shortening and oxidative stress.[1]
Senescence-related changes in intestinal epithelial organoids derived from aged mice
gene set enrichment analysis (GSEA) demonstrated that the gene sets associated with the Wnt signaling pathway, stem cell signature and DNA replication were significantly suppressed in intestinal epithelial organoids established from aged mice. These results suggested that suppression of Lgr[5] induces inactivation of the Wnt signaling pathway and a decrease of the stem cell signature, resulting in cellular senescence and a decrease of cell proliferation in intestinal epithelial organoids derived from aged mice
Summary
Cells are continuously exposed to aging-associated phenomena such as telomere shortening and oxidative stress.[1] In various organs, homeostatic tissue maintenance and regenerative responses to injury depend on tissue-specific stem cells that have the capacity to both self-renew and differentiate into mature daughter cells. The life-long persistence of stem cells in the body makes them susceptible to accumulated cellular damage, which can lead to cell death, senescence or loss of regenerative function. Tissue-specific stem cells have been found to undergo changes with age, resulting in irregular responses to tissue injury, dysregulation of proliferation and decreased functional capacity, a phenomenon referred to as “stem cell aging”.2. In order to achieve this, it would be necessary to understand the molecular processes controlling stem cell survival, self-renewal, quiescence, proliferation, and commitment to specific differentiated cell lineages. Investigation of these agingrelated processes has been difficult because of the lack of in vitro models that reflect the features of tissue-specific stem cells
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