Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

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

doi:10.1016/j.stem.2007.02.001

Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

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

Research output: Contribution to journal › Article › peer-review

720 Scopus citations

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.

Original language	English (US)
Pages (from-to)	101-112
Number of pages	12
Journal	Cell Stem Cell
Volume	1
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2007.02.001
State	Published - Jun 7 2007
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2007.02.001

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Miyamoto, K., Araki, K. Y., Naka, K., Arai, F., Takubo, K., Yamazaki, S., Matsuoka, S., Miyamoto, T., Ito, K., Ohmura, M., Chen, C., Hosokawa, K., Nakauchi, H., Nakayama, K., Nakayama, K. I., Harada, M., Motoyama, N., Suda, T., & Hirao, A. (2007). Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool. Cell Stem Cell, 1(1), 101-112. https://doi.org/10.1016/j.stem.2007.02.001

Miyamoto, K, Araki, KY, Naka, K, Arai, F, Takubo, K, Yamazaki, S, Matsuoka, S, Miyamoto, T, Ito, K, Ohmura, M, Chen, C, Hosokawa, K, Nakauchi, H, Nakayama, K, Nakayama, KI, Harada, M, Motoyama, N, Suda, T & Hirao, A 2007, 'Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool', Cell Stem Cell, vol. 1, no. 1, pp. 101-112. https://doi.org/10.1016/j.stem.2007.02.001

@article{1501e8db359c41b0b77584a8ccc7580e,

title = "Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool",

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.",

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

note = "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. ",

year = "2007",

month = jun,

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doi = "10.1016/j.stem.2007.02.001",

language = "English (US)",

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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.

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JO - Cell Stem Cell

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ER -

Foxo3a Is Essential for Maintenance of the Hematopoietic Stem Cell Pool

Abstract

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