FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging
FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging
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DOI：
10.1182/blood-2008-05-159848
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发表时间：
2008-12-01
期刊：
影响因子：
20.3
通讯作者：
Suda, Toshio
中科院分区：
文献类型：
--
作者：
Miyamoto, Kana;Miyamoto, Takeshi;Suda, Toshio
组织特异性干细胞的应激或老化被认为是老年人组织稳态下降的核心，尽管人们对造血干细胞(HSC)衰老和应激抵抗的分子机制知之甚少。在这里，我们报告了缺乏转录因子叉头盒O3a(FOXO3a)的小鼠在骨髓抑制应激条件下的造血恢复过程中，与抑制细胞增殖负调控因子、芽胞相关的Ena/Vasp同源1区含蛋白2(Spred2)以及AKT和ERK激活相关的中性粒细胞增多。与老龄野生型小鼠相比，Foxo3a基因缺陷老龄小鼠的中性粒细胞增多。在FOXO3a基因缺陷老龄小鼠的HSC中检测到AKT和ERK的激活和Spred2的抑制。Spred2基因缺陷的小鼠在骨髓抑制应激后的造血恢复过程中也出现了中性粒细胞反应，这表明FOXO3a通过负反馈的增殖途径在HSC的维持、完整性和应激抵抗中起着关键作用。这将为衰老和应激条件下的造血动态平衡提供新的见解。(血。2008年；112：4485-4493)
Stress or aging of tissue-specific stem cells is considered central to the decline of tissue homeostasis in the elderly, although little is known of molecular mechanisms underlying hematopoietic stem cell (HSC) aging and stress resistance. Here, we report that mice lacking the transcription factor forkhead box O3a (FoxO3a) develop neutrophilia associated with inhibition of the up-regulation of negative regulator of cell proliferation, Sprouty-related Ena/VASP homology 1 domain containing proteins 2 (Spred2) and AKT and ERK activation, in HSCs during hematopoietic recovery following myelosuppressive stress conditions. Compared with aged wild-type mice, more severe neutrophilia was also observed in aged Foxo3a-deficient mice. AKT and ERK activation and inhibition of Spred2 were detected in HSCs from aged FoxO3a-deficient mice. Spred2-deficient mice also developed neutrophilia during hematopoietic recovery following myelosuppressive stress, indicating that FoxO3a plays a pivotal role in maintenance, integrity, and stress resistance of HSCs through negative feedback pathways for proliferation. This will provide new insight into the hematopoietic homeostasis in conditions of aging and stress. (Blood. 2008;112: 4485-4493)