Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany; University of Heidelberg, 69120 Heidelberg, Germany.
Molecular Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany.
Cell. 2019 Mar 7;176(6):1407-1419.e14. doi: 10.1016/j.cell.2019.01.040. Epub 2019 Feb 28.
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.
体干细胞的功能随年龄增长而下降。了解这种下降的分子基础是对抗与年龄相关疾病的关键。在这里，我们报告了衰老小鼠大脑中的神经干细胞（NSC）数量的急剧下降。我们发现，这种较小的干细胞库通过静止增加得到保护，从而使老年 NSC 更能抵抗损伤大脑的再生。然而，一旦被激活，年轻和老年 NSC 显示出相似的增殖和分化能力。NSC 的单细胞转录组学表明，衰老对 NSC 的改变很小。在衰老的大脑中，龛位衍生的炎症信号和 Wnt 拮抗剂 sFRP5 诱导静止。事实上，干预以中和它们会在稳态和损伤后增加老年 NSC 的激活。我们的研究确定了静止是由龛位施加于老年 NSC 的一个关键特征，并揭示了激活 NSC 以修复衰老大脑的方法。
