Genome instability of ageing stem cells--Induction and defence mechanisms.
Genome instability of ageing stem cells--Induction and defence mechanisms.
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DOI：
10.1016/j.arr.2015.01.004
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发表时间：
2015-09
影响因子：
13.1
通讯作者：
Sperka T
中科院分区：
文献类型：
--
作者：
Burkhalter MD;Rudolph KL;Sperka T
干细胞功能随着年龄的增长而下降。DNA损伤和突变在衰老的干细胞中积累。无法修复DNA可能导致干细胞库过早耗尽。检查点功能在年轻时保持基因组完整性。强制检查点诱导有助于干细胞老化。哺乳动物机体由具有不同程度的自我更新和再生能力的组织类型组成。在大多数器官中，自我更新的组织特异性干细胞和祖细胞有助于器官维持，维持功能性干细胞库以保持器官稳态至关重要。各种条件，如组织损伤，应激反应和再生挑战干细胞库重建稳态（图1）。然而，随着年龄的增长，成体干细胞的功能下降，基因组突变积累。这些缺陷影响不同的细胞反应途径，并导致再生，应激耐受性和器官功能受损，以及与衰老相关的疾病和癌症的发展风险增加。基因组的维持对于保持干细胞功能和降低与衰老相关的功能障碍和病理的风险似乎是至关重要的。在这篇综述中，我们讨论了干细胞功能障碍和DNA损伤累积之间的因果关系，干细胞如何保持基因组完整性的不同策略，以及这些过程在衰老过程中如何受到影响。
Stem cell function is declining with increasing age. DNA lesions and mutations accumulate in ageing stem cells. Inability to repair DNA can lead to premature depletion of stem cell pools. Checkpoint function preserves genomic integrity at young age. Enforced checkpoint induction contributes to stem cell ageing. The mammalian organism is comprised of tissue types with varying degrees of self-renewal and regenerative capacity. In most organs self-renewing tissue-specific stem and progenitor cells contribute to organ maintenance, and it is vital to maintain a functional stem cell pool to preserve organ homeostasis. Various conditions like tissue injury, stress responses, and regeneration challenge the stem cell pool to re-establish homeostasis (Fig. 1). However, with increasing age the functionality of adult stem cells declines and genomic mutations accumulate. These defects affect different cellular response pathways and lead to impairments in regeneration, stress tolerance, and organ function as well as to an increased risk for the development of ageing associated diseases and cancer. Maintenance of the genome appears to be of utmost importance to preserve stem cell function and to reduce the risk of ageing associated dysfunctions and pathologies. In this review, we discuss the causal link between stem cell dysfunction and DNA damage accrual, different strategies how stem cells maintain genome integrity, and how these processes are affected during ageing.