TY - JOUR
T1 - Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool
AU - Miyamoto, Kana
AU - Araki, Kiyomi Y.
AU - Naka, Kazuhito
AU - Arai, Fumio
AU - Takubo, Keiyo
AU - Yamazaki, Satoshi
AU - Matsuoka, Sahoko
AU - Miyamoto, Takeshi
AU - Ito, Keisuke
AU - Ohmura, Masako
AU - Chen, Chen
AU - Hosokawa, Kentaro
AU - Nakauchi, Hiromitsu
AU - Nakayama, Keiko
AU - Nakayama, Keiichi I.
AU - Harada, Mine
AU - Motoyama, Noboru
AU - Suda, Toshio
AU - Hirao, Atsushi
N1 - Funding Information:
We thank Dr. Atsushi Iwama for helpful discussion and Ayami Ono and Yukari Yamada for technical assistance. A.H. was supported by the Grant-in-Aid for Stem Cell Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. T.S. was supported by the Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. N.M. was supported by the Grant-in-Aid for Comprehensive Research on Aging and Health from the Ministry of Health, Labour, and Welfare, Japan. The authors declare that they have no competing financial interests.
PY - 2007/6/7
Y1 - 2007/6/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/34249882777
UR - https://www.scopus.com/pages/publications/34249882777#tab=citedBy
U2 - 10.1016/j.stem.2007.02.001
DO - 10.1016/j.stem.2007.02.001
M3 - Article
C2 - 18371339
AN - SCOPUS:34249882777
SN - 1934-5909
VL - 1
SP - 101
EP - 112
JO - Cell stem cell
JF - Cell stem cell
IS - 1
ER -