TY - JOUR
T1 - Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging
AU - Uchida, Ryoei
AU - Saito, Yoshimasa
AU - Nogami, Kazuki
AU - Kajiyama, Yohei
AU - Suzuki, Yukana
AU - Kawase, Yasuhiro
AU - Nakaoka, Toshiaki
AU - Muramatsu, Toshihide
AU - Kimura, Masaki
AU - Saito, Hidetsugu
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant Number 16K13051 (to Y.Sa.).
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41514-018-0031-5
DO - 10.1038/s41514-018-0031-5
M3 - Article
AN - SCOPUS:85057624984
SN - 2056-3973
VL - 5
JO - npj Aging and Mechanisms of Disease
JF - npj Aging and Mechanisms of Disease
IS - 1
M1 - 1
ER -
