表观遗传沉默Lgr5可诱导肠上皮类器官在衰老过程中衰老。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
NPJ Aging and Mechanisms of Disease Pub Date : 2018-12-01 eCollection Date: 2019-01-01 DOI:10.1038/s41514-018-0031-5
Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito
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引用次数: 22

摘要

为了了解干细胞衰老的分子特征,我们建立了来自年轻和老年小鼠的肠上皮类器官,并研究了它们的衰老和表观遗传状态的变化。衰老相关的变化包括衰老相关β-半乳糖苷酶的积累和DNA去甲基化对Cdkn1a (p21)的上调。我们还证明了重要的干细胞标志物Lgr5通过组蛋白H3赖氨酸27的三甲基化被表观遗传沉默,诱导Wnt信号的抑制和衰老小鼠类器官细胞增殖的减少。我们进一步用NAD+的关键中间体烟酰胺单核苷酸(NMN)处理老年小鼠的肠上皮类器官。结果显示,类器官显示出更高的NAD+水平,细胞增殖能力增强,Lgr5激活和衰老相关基因抑制,表明NMN治疗可以改善肠道上皮细胞的衰老相关变化。这些发现表明,来自老年动物的类器官可能是研究干细胞衰老的分子机制和开发某种形式的抗衰老干预的有力研究工具,从而有助于延长健康预期寿命。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Epigenetic silencing of <i>Lgr5</i> induces senescence of intestinal epithelial organoids during the process of aging.

Epigenetic silencing of <i>Lgr5</i> induces senescence of intestinal epithelial organoids during the process of aging.

Epigenetic silencing of <i>Lgr5</i> induces senescence of intestinal epithelial organoids during the process of aging.

Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging.

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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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
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0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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