Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

Keio University, Edo, Tokyo, Japan
Cell stem cell (Impact Factor: 22.27). 07/2007; 1(1):101-12. DOI: 10.1016/j.stem.2007.02.001
Source: PubMed


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.

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Available from: Kazuhito Naka, Oct 28, 2015
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    • "The clones without excision of Foxo alleles held competitive advantage and quickly took over the hematopoietic system. Importantly, it was striking that, as seen in other genetic models (Ito et al., 2004; Miyamoto et al., 2007; Nijnik et al., 2007; Walter et al., 2015), the molecular and functional changes following Foxo1/3/4 deletion were significantly more pronounced in primitive HSC compartment. This indicates that DDR pathways are very important in preserving the pool of quiescent HSCs and entry into cell cycle coupled with alteration in DDR pathways can lead to their exhaustion (Fig. 5). "
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    • "In this study, male WT, Foxo3 +/– , and Foxo3 –/– mice were subjected to 30% DR initiated at 12 weeks of age. The genetic background of the mice was C57BL6 (Miyamoto et al., 2007). Control mice were maintained under the ad libitum (AL) condition. "
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    • "ROS reduce self-renewal by activation of the cyclin dependent kinase (CDK) inhibitor p16 Ink4a and the tumour suppressor Rb, and block quiescence by induction of the stress response kinase p38 (Fig. 4; Ito et al., 2004; Ito et al., 2006). Furthermore, deletions of Forkhead box O (Foxo) transcription factors, which aid in detoxification of ROS, also compromise HSC self-renewal and quiescence by stimulating Rb and p53 (Miyamoto et al., 2007; Tothova et al., 2007; Yalcin et al., 2008). However, treatment with the ROS scavenger N-acetylcysteine rescues HSC maintenance (Chen et al., 2008; Ito et al., 2004; Tothova et al., 2007; Yalcin et al., 2008). "
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