Foxo3a is essential for maintenance of the hematopoietic stem cell pool
Foxo3a is essential for maintenance of the hematopoietic stem cell pool
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DOI：
10.1016/j.stem.2007.02.001
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发表时间：
2007-07-01
期刊：
影响因子：
23.9
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
--
作者：
Miyamoto, Kana;Araki, Kiyomi Y.;Hirao, Atsushi
造血干细胞（HSC）在骨髓微环境中维持未分化的静止状态。在这里，我们表明 Foxo3a 是一种叉头转录因子，作用于 PTEN/PI3K/Akt 通路下游，对于 HSC 自我更新至关重要。我们生成了基因靶向的 Foxo3a(-/-) 小鼠，结果表明，尽管 Foxo3a(-/-) 造血祖细胞的增殖和分化正常，但长期共培养 Foxo3a(-/-) 骨髓细胞和基质细胞时，集落形成细胞的数量减少。 Foxo3a(-/-) HSC 在竞争性移植试验中支持长期造血重建的能力也受到损害。 Foxo3a(-/-) HSC 还表现出 p38MAPK 磷酸化增加、ROS 升高、静止维持缺陷以及对细胞周期特异性骨髓毒性损伤的敏感性增强。最后，与同窝对照小鼠相比，老年 Foxo3a(-/-) 小鼠的 HSC 频率显着降低。我们的结果表明 Foxo3a 在维持 HSC 库中发挥着关键作用。
Hematopoietic stem cells (HSCs) are maintained in an undifferentiated quiescent state within a bone marrow niche. Here we show that Foxo3a, a forkhead transcription factor that acts downstream of the PTEN/PI3K/Akt pathway, is critical for HSC self-renewal. We generated gene-targeted Foxo3a(-/-) mice and showed that, although the proliferation and differentiation of Foxo3a(-/-) hematopoietic progenitors were normal, the number of colony-forming cells present in long-term cocultures of Foxo3a(-/-) bone marrow cells and stromal cells was reduced. The ability of Foxo3a(-/-) HSCs to support long-term reconstitution of hematopoiesis in a competitive transplantation assay was also impaired. Foxo3a(-/-) HSCs also showed increased phosphorylation of p38MAPK, an elevation of ROS, defective maintenance of quiescence, and heightened sensitivity to cell-cycle-specific myelotoxic injury. Finally, HSC frequencies were significantly decreased in aged Foxo3a(-/-) mice compared to the littermate controls. Our results demonstrate that Foxo3a plays a pivotal role in maintaining the HSC pool.