Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age
Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age
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DOI：
10.1038/nature05862
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发表时间：
2007-06-07
期刊：
影响因子：
64.8
通讯作者：
Weissman, Irving L.
中科院分区：
文献类型：
--
作者：
Rossi, Derrick J.;Bryder, David;Weissman, Irving L.
维持组织动态平衡的能力减弱是衰老的主要生理特征。由于干细胞调节组织的动态平衡，干细胞储备的耗尽和/或干细胞功能的减弱被认为是导致衰老的原因(1)。进一步研究表明，DNA累积损伤可能是年龄依赖性干细胞衰退的主要机制[2]。我们通过检测缺乏核苷酸切除修复(3，4)、端粒维持(5，6)和非同源末端连接(7，8)等几种基因组维持途径的小鼠的造血干细胞储备和随年龄增长的功能来检验这些假说。在这里，我们发现，尽管这些途径的缺陷并不会随着年龄的增长而耗尽干细胞储备，但在应激条件下，干细胞的功能能力会受到严重影响，导致重建和增殖潜力的丧失，自我更新的减弱，细胞凋亡的增加，最终导致功能衰竭。此外，我们提供的证据表明，在野生型干细胞中，内源性DNA损伤随着年龄的增长而累积。这些数据与DNA损伤累积相一致，DNA损伤累积是干细胞老化的一种生理机制，可能导致衰老组织在暴露于急性应激或损伤后恢复内稳的能力减弱。
A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing(1). It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline(2). We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair(3,4), telomere maintenance(5,6) and non-homologous end-joining(7,8). Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.