The Fanconi anemia pathway is required for efficient repair of stress-induced DNA damage in haematopoietic stem cells
The Fanconi anemia pathway is required for efficient repair of stress-induced DNA damage in haematopoietic stem cells
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DOI：
10.1080/15384101.2015.1068474
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发表时间：
2015-09-02
期刊：
影响因子：
4.3
通讯作者：
Milsom, Michael D.
中科院分区：
文献类型：
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作者：
Kaschutnig, Paul;Bogeska, Ruzhica;Milsom, Michael D.
在再生组织中，衰老的特征是器官功能的进行性普遍退化，被认为是由功能性成体干细胞的逐渐耗尽驱动的。虽然可能存在导致干细胞功能随着年龄增长而受损的多因素机制，但干细胞隔室内DNA损伤的积累可能对这一过程做出重大贡献。然而，不同组织特异性干细胞隔室内DNA损伤的生理来源仍有待确定，暴露于这种损伤的干细胞的命运也是如此。使用造血系统作为一个模型器官，我们最近已经表明，某些形式的生理应激，如感染相关的炎症和大量失血，导致诱导的生物相关水平的DNA损伤的造血干细胞（HSC），通过显着增加的增殖指数，这个通常静止的细胞群体。(1)我们还能够证明，这种应激相关的DNA损伤足以完全耗尽HSC，并在范可尼贫血（FA）敲除小鼠模型中促进严重再生障碍性贫血（SAA），这损害了复制相关的DNA修复。在这篇额外的观点文章中，我们扩展了以前的工作，表明FA小鼠即使在极端高龄也不会自发地发展出与SAA一致的造血表型。这表明HSC静止限制了衰老过程中DNA损伤的获得，并保持了干细胞库的功能完整性。根据这一假设，我们提供了一个延长的时间过程分析的响应FA敲除小鼠慢性炎症应激，并表明，强制HSC增殖导致一个高度渗透SAA表型，这非常类似于疾病的进展FA患者。
Within regenerating tissues, aging is characterized by a progressive general deterioration of organ function, thought to be driven by the gradual depletion of functional adult stem cells. Although there are probably multifactorial mechanisms that result in compromized stem cell functionality with advancing age, the accumulation of DNA damage within the stem cell compartment is likely to make a major contribution to this process. However, the physiologic source of DNA damage within the different tissue specific stem cell compartments remains to be determined, as does the fate of stem cells exposed to such damage. Using the haematopoietic system as a model organ, we have recently shown that certain forms of physiologic stress, such as infection-associated inflammation and extensive blood loss, leads to the induction of biologically relevant levels of DNA damage in haematopoietic stem cells (HSCs) by dramatically increasing the proliferative index of this normally quiescent cell population.(1) We were also able to demonstrate that such stress-associated DNA damage was sufficient to completely deplete HSCs and promote severe aplastic anemia (SAA) in the Fanconi anemia (FA) knockout mouse model, which has compromized replication-associated DNA repair. In this Extra Views article, we extend this previous work to show that FA mice do not spontaneously develop a haematopoietic phenotype consistent with SAA, even at extreme old age. This suggests that HSC quiescence restricts the acquisition of DNA damage during aging and preserves the functional integrity of the stem cell pool. In line with this hypothesis, we provide an extended time course analysis of the response of FA knockout mice to chronic inflammatory stress and show that enforced HSC proliferation leads to a highly penetrant SAA phenotype, which closely resembles the progression of the disease in FA patients.