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. 2007 Jun 7;1(1):101-112.
doi: 10.1016/j.stem.2007.02.001.

Foxo3a is essential for maintenance of the hematopoietic stem cell pool

Kana Miyamoto  1 , Kiyomi Y Araki  2 , Kazuhito Naka  3 , Fumio Arai  4 , Keiyo Takubo  4 , Satoshi Yamazaki  5 , Sahoko Matsuoka  4 , Takeshi Miyamoto  4 , Keisuke Ito  4 , Masako Ohmura  3 , Chen Chen  2 , Kentaro Hosokawa  4 , Hiromitsu Nakauchi  5 , Keiko Nakayama  6 , Keiichi I Nakayama  7 , Mine Harada  8 , Noboru Motoyama  9 , Toshio Suda  10 , Atsushi Hirao  11
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Free article

Foxo3a is essential for maintenance of the hematopoietic stem cell pool

Kana Miyamoto et al. Cell Stem Cell. .
Free article

Abstract

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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