Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine
Calorie Restriction Increases the Number of Competing Stem Cells and Decreases Mutation Retention in the Intestine
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DOI：
10.1016/j.celrep.2020.107937
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发表时间：
2020-07-21
期刊：
影响因子：
8.8
通讯作者：
van Rheenen, Jacco
中科院分区：
文献类型：
--
作者：
Bruens, Lotte;Ellenbroek, Saskia Inge Johanna;van Rheenen, Jacco
热量限制（CR）通过几种细胞内机制延长寿命，包括增加DNA修复，导致更少的导致年龄相关病理的DNA突变。然而，它仍然是未知的CR如何在组织水平上的突变保留的作用。在这里，我们使用Cre-mediated的五彩纸屑报告基因的DNA重组作为中性突变的代理，并通过活体显微镜观察这些突变，以确定CR如何影响肠道中突变的保留。我们发现，CR导致功能性Lgr 5（+）干细胞数量增加，这些干细胞竞争生态位，导致干细胞竞争较慢但更强。因此，携带中性或Apc突变的干细胞会遇到更多的野生型竞争者，从而增加了它们随着时间的推移而从生态位中消失的机会。因此，我们的数据表明，CR不仅影响突变的获得，而且还导致肠中突变的保留较低。
Calorie restriction (CR) extends lifespan through several intracellular mechanisms, including increased DNA repair, leading to fewer DNA mutations that cause age-related pathologies. However, it remains unknown how CR acts on mutation retention at the tissue level. Here, we use Cre-mediated DNA recombination of the confetti reporter as proxy for neutral mutations and follow these mutations by intravital microscopy to identify how CR affects retention of mutations in the intestine. We find that CR leads to increased numbers of functional Lgr5(+) stem cells that compete for niche occupancy, resulting in slower but stronger stem cell competition. Consequently, stem cells carrying neutral or Apc mutations encounter more wild-type competitors, thus increasing the chance that they get displaced from the niche to get lost over time. Thus, our data show that CR not only affects the acquisition of mutations but also leads to lower retention of mutations in the intestine.