Details

Autor(en) / Beteiligte

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

Titel

Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

Ist Teil von

• Cell stem cell, 2007-06, Vol.1 (1), p.101-112

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2007

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.