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Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

2007; Elsevier BV; Volume: 1; Issue: 1 Linguagem: Inglês

10.1016/j.stem.2007.02.001

1934-5909

Kana Miyamoto, Kiyomi Y. Araki, Kazuhito Naka, Fumio Arai, Keiyo Takubo, Satoshi Yamazaki, Sahoko Matsuoka, Takeshi Miyamoto, Keisuke Ito, Masako Ohmura, Chen Chen, Kentaro Hosokawa, Hiromitsu Nakauchi, Keiko Nakayama, Keiichi I. Nakayama, Mine Harada, Noboru Motoyama, Toshio Suda, Atsushi Hirao,

Hippo pathway signaling and YAP/TAZ

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.