Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, 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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    • "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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    • "As a transcriptional factor, FOXO3 is known to regulate various cellular processes such as cell cycle (14,15), cellular apoptosis (16–19), DNA damage repair (20,21), stress responses (15,22,23), metabolism (24), aging (25) and tumor suppression in mammalian cells (12,18,26). The results from gene knockout exhibit key functions of FOXO family members in tumor suppression (27) and in preventing the decline of the hematopoietic stem cell pool (28). The FOXO3 protein in cancer cells can be regulated by various protein modification mechanisms such as phosphorylation, acetylation and ubiquitination (25,29–31). "
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