2010 Fiscal Year Final Research Report
Molecular mechanisms for hematopoietic stem cells by HIF-1/VHL regulatory system
| Project/Area Number |
21790925
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | Keio University |
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Principal Investigator |
TAKUBO Keiyo Keio University, 医学部, 助教 (50502788)
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| Project Period (FY) |
2009 – 2010
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| Keywords | 造血幹細胞 / 低酸素 / 静止期 / 老化 |
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| Research Abstract |
Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Mammalian HSCs are kept quiescent in the endosteal niche, a hypoxic zone of the bone marrow (BM). We found that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) protein. In HIF-1alpha-deficient mice, the HSCs lost their cell cycle quiescence and HSC numbers decreased during various stress settings including bone marrow transplantation, myelosuppression, or aging, in a p16Ink4a/p19Arf-dependent manner. Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation capacity. In contrast, monoallelic loss of VHL induced cell cycle quiescence and improved BM engraftment during bone marrow transplantation. These data indicate that HSCs maintain cell cycle quiescence through the precise regulation of HIF-1alpha levels.
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Research Products
(21 results)
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[Journal Article] A germ cell specific gene, Prmt5 works as somatic cell reprogramming.2011
Author(s)
Nagamatsu G, Kosaka T, Kawasumi M, Kinoshita T, Takubo K, Akiyama H, Sudo T, Kobayashi T, Oya M, Suda T.
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Journal Title
J Biol Chem. [Epub ahead ofprint]
Peer Reviewed
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[Journal Article] Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation.2011
Author(s)
Honda H, Takubo K, Oda H, Kosaki K, Tazaki T, Yamasaki N, Miyazaki K, Moore KA, Honda Z, Suda T, Lemischka IR.
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Journal Title
Proc Natl Acad Sci USA. 108(6)Epub
Pages: 2468-2473
Peer Reviewed
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[Journal Article] Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.2010
Author(s)
Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M, Suda T.
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Journal Title
Cell Stem Cell. 7(3)
Pages: 391-402
Peer Reviewed
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[Journal Article] von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina.2010
Author(s)
Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon MC, Johnson RS, Suematsu M, Tsubota K, Ishida S, Goda N, Suda T, Okano H.
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Journal Title
Development 137(9)
Pages: 1563-1571
Peer Reviewed
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[Journal Article] Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow.2010
Author(s)
Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y, Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T.
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Journal Title
Cell Stem Cell. 6(3)
Pages: 194-198
Peer Reviewed
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[Journal Article] Craniofacial malformation in R-spondin2 knockout mice.2009
Author(s)
Yamada W, Nagao K, Horikoshi K, Fujikura A, Ikeda E, Inagaki Y, Kakitani M, Tomizuka K, Miyazaki H, Suda T, Takubo K.
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Journal Title
Biochem Biophys Res Commun. 381(3)Epub
Pages: 453-458
Peer Reviewed
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