Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Blood. 2010 Dec 2;116(23):4806-14. doi: 10.1182/blood-2010-06-288589. Epub 2010 Aug 17.
Little is known about whether autophagic mechanisms are active in hematopoietic stem cells (HSCs) or how they are regulated. FIP200 (200-kDa FAK-family interacting protein) plays important roles in mammalian autophagy and other cellular functions, but its role in hematopoietic cells has not been examined. Here we show that conditional deletion of FIP200 in hematopoietic cells leads to perinatal lethality and severe anemia. FIP200 was cell-autonomously required for the maintenance and function of fetal HSCs. FIP200-deficient HSC were unable to reconstitute lethally irradiated recipients. FIP200 ablation did not result in increased HSC apoptosis, but it did increase the rate of HSC proliferation. Consistent with an essential role for FIP200 in autophagy, FIP200-null fetal HSCs exhibited both increased mitochondrial mass and reactive oxygen species. These data identify FIP200 as a key intrinsic regulator of fetal HSCs and implicate a potential role for autophagy in the maintenance of fetal hematopoiesis and HSCs.
目前对于自噬机制在造血干细胞（HSCs）中是否活跃以及它们是如何被调控的知之甚少。FIP200（200kDaFAK 家族相互作用蛋白）在哺乳动物自噬和其他细胞功能中发挥着重要作用，但它在造血细胞中的作用尚未被研究过。在这里，我们发现造血细胞中 FIP200 的条件缺失导致围产期致死和严重贫血。FIP200 细胞自主地维持和功能对于胎儿 HSCs 是必需的。FIP200 缺陷的 HSC 无法重建致死性辐射的受者。FIP200 缺失不会导致 HSC 凋亡增加，但会增加 HSC 的增殖率。与 FIP200 在自噬中的关键作用一致，FIP200 缺失的胎儿 HSC 表现出线粒体质量和活性氧的增加。这些数据表明 FIP200 是胎儿 HSC 的关键内在调节因子，并暗示自噬在维持胎儿造血和 HSC 中可能发挥作用。
