Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain
Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain
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DOI：
10.1016/j.cell.2019.01.040
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发表时间：
2019-03-07
期刊：
影响因子：
64.5
通讯作者：
Martin-Villalba, Ana
中科院分区：
文献类型：
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作者：
Kalamakis, Georgios;Bruene, Daniel;Martin-Villalba, Ana
随着年龄的增长，体干细胞的功能下降。了解这种下降的分子基础是对抗年龄相关疾病的关键。在这里，我们报告了一个戏剧性的下降，在神经干细胞（NSC）的数量在老龄小鼠的大脑。我们发现，这种较小的干细胞库通过增加静止状态而免受完全耗尽，这使得旧的NSC对再生受损的大脑更具抵抗力。然而，一旦被激活，年轻和年老的NSC表现出相似的增殖和分化能力。神经干细胞的单细胞转录组学表明，衰老对神经干细胞的影响最小。在衰老的大脑中，小生境衍生的炎症信号和Wnt拮抗剂sFRP5诱导静止。事实上，中和它们的干预增加了稳态期间和损伤后旧NSC的激活。我们的研究确定了静止作为由生态位施加的老年NSC的关键特征，并揭示了激活NSC以修复老化大脑的方法。
The function of somatic stem cells declines with age. Understanding the molecular underpinnings of this decline is key to counteract age-related disease. Here, we report a dramatic drop in the neural stem cells (NSCs) number in the aging murine brain. We find that this smaller stem cell reservoir is protected from full depletion by an increase in quiescence that makes old NSCs more resistant to regenerate the injured brain. Once activated, however, young and old NSCs show similar proliferation and differentiation capacity. Single-cell transcriptomics of NSCs indicate that aging changes NSCs minimally. In the aging brain, niche-derived inflammatory signals and the Wnt antagonist sFRP5 induce quiescence. Indeed, intervention to neutralize them increases activation of old NSCs during homeostasis and following injury. Our study identifies quiescence as a key feature of old NSCs imposed by the niche and uncovers ways to activate NSCs to repair the aging brain.