Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
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DOI：
10.1016/j.cell.2009.03.037
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发表时间：
2009-06-12
期刊：
影响因子：
64.5
通讯作者：
Nishimura, Emi K.
中科院分区：
文献类型：
--
作者：
Inomata, Ken;Aoto, Takahiro;Nishimura, Emi K.
由于DNA损伤的积累而导致的体细胞干细胞耗竭与衰老相关表型的出现有关。毛发变白是哺乳动物衰老的典型标志，是由黑素干细胞（MSC）随着年龄的增长而不完全维持引起的。在这里，我们报告说，不可修复的DNA损伤，电离辐射引起的，废除小鼠骨髓间充质干细胞的更新。令人惊讶的是，DNA损伤反应触发MSC分化为生态位中的成熟黑素细胞，而不是诱导其凋亡或衰老。由此产生的MSC消耗导致不可逆的头发变白。此外，共济失调-毛细血管扩张突变（ATM）（DNA损伤反应的中心转导激酶）的缺乏使MSC对异位分化敏感，表明该激酶通过充当“干性检查点”来保护MSC免于其过早分化，以维持干细胞的质量和数量。
Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint'' to maintain the stem cell quality and quantity.