Autophagy maintains the metabolism and function of young and old stem cells.
Autophagy maintains the metabolism and function of young and old stem cells.
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DOI：
10.1038/nature21388
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发表时间：
2017-03-09
期刊：
影响因子：
64.8
通讯作者：
Passegué E
中科院分区：
文献类型：
--
作者：
Ho TT;Warr MR;Adelman ER;Lansinger OM;Flach J;Verovskaya EV;Figueroa ME;Passegué E
随着年龄的增长，造血干细胞（HSC）失去了再生血液系统的能力，并促进疾病的发展。自噬与健康和长寿相关，对于保护HSC免受代谢应激至关重要。在这里，我们发现HSC中自噬的丧失导致线粒体的积累和活化的代谢状态，这主要通过表观遗传失调来驱动加速的骨髓分化，并损害HSC的自我更新活性和再生潜力。引人注目的是，老年小鼠中的大多数HSC都具有这些改变的代谢和功能特征。然而，约1/3的老年HSC表现出高自噬水平，并保持低代谢状态，具有与健康年轻HSC相似的强大长期再生潜力。我们的研究结果表明，自噬通过清除活跃、健康的线粒体来积极抑制HSC代谢，以维持静止和干性，并且随着年龄的增长，自噬变得越来越必要，以保持老年HSC的再生能力。
With age, hematopoietic stem cells (HSCs) lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting HSCs from metabolic stress. Here, we show that loss of autophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs HSC self-renewal activity and regenerative potential. Strikingly, the majority of HSCs in aged mice share these altered metabolic and functional features. However, ~ 1/3 of aged HSCs exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young HSCs. Our results demonstrate that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old HSCs.