2011 Fiscal Year Final Research Report
Elucidation of the mechanisms underlying maintenance of hematopoietic stem cell hibernation
| Project/Area Number |
21249059
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
OTSU Makoto 東京大学, 医科学研究所, 特任准教授 (30361330)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 造血幹細胞 / CD34陽性細胞 / 骨髄微小環境 / 非髄鞘シュワン細胞 / GFAP陽性細胞 / 白血病幹細胞 |
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| Research Abstract |
Hematopoietic stem cells(HSCs) reside in a bone marrow niche in a nondividing state, from which they occasionally arise to undergo cell division. Yet, the mechanism underlying this unique feature remains largely unknown. We screened candidate niche signals that inhibit lipid raft clustering, and identified that transforming growth factor-β(TGF-β) efficiently induces HSC hibernation ex vivo. From these data, we uncovered a critical role for TGF-βas a candidate niche signal in the control of HSC hibernation and provided TGF-βas a novel tool for ex vivo modeling of the HSC niche. TGF-βis produced as a latent form by a variety of cells, so we next searched for those that express activator molecules for latent TGF-β. Nonmyelinating Schwann cells in bone marrow(BM) proved responsible for the activation. These glial cells ensheathed autonomic nerves, expressed HSC niche factor genes, and were in contact with a substantial proportion of HSCs. Autonomic nerve denervation reduced the number of these active TGF-β-producing cells and led to rapid loss of HSCs from BM. Collectively, we for the first time demonstrated that glial cells are components of a BM niche and maintain HSC hibernation by regulating activation of latent TGF-β.
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[Journal Article] A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage2012
Author(s)
Wang J, Sun Q, Morita Y, Jiang H, Gros A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL.
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Journal Title
Cell
Volume: 148
Pages: 1001-1014
Peer Reviewed
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[Journal Article] Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells2011
Author(s)
Umemoto T, Yamato M, Ishihara J, Shiratsuchi Y, Utsumi M, Morita Y, Tsukui H, Terasawa M, Shibata T, Nishida K, Kobayashi Y, Petrich BG, Nakauchi H, Eto K, Okano T.
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Journal Title
Blood
Volume: 119
Pages: 83-94
Peer Reviewed
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[Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia2011
Author(s)
Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki
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Journal Title
Nature
Volume: 478
Pages: 64-69
Peer Reviewed
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[Journal Article] Hair follicle stem cells provide a functional niche for melanocyte stem cells2011
Author(s)
Tanimura S, Tadokoro Y, Inomata K, Binh NT, Nishie W, Yamazaki S, Nakauchi H, Tanaka Y, McMillan JR, Sawamura D, Yancey K, Shimizu H, Nishimura EK
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Journal Title
Cell Stem Cell
Volume: 8
Pages: 177-87
Peer Reviewed
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[Journal Article] Development of defective and persistent sendai virus vector : a unique gene delivery/expression system ideal for cell reprogramming2011
Author(s)
Nishimura K, Sano M, Ohtaka M, Furuta B, Umemura Y, Nakajima Y, Ikehara Y, Kobayashi T, Segawa H, Takayasu S, Sato H, Motomura K, Uchida E, Kanayasu-Toyoda T, Asashima M, Nakauchi H, Yamaguchi T, Nakanishi M
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Journal Title
J Biol Chem
Volume: 11
Pages: 4760
Peer Reviewed
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[Journal Article] Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells2010
Author(s)
Takayama N, Nishimura S, Nakamura S, Shimizu T, Ohnishi R, Endo H, Yamaguchi T, Otsu M, Nishimura K, Nakanishi M, Sawaguchi A, Nagai R, Takahashi K, Yamanaka S, Nakauchi H, Eto K
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Journal Title
J Exp Med
Volume: 207
Pages: 2817-30
Peer Reviewed
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[Journal Article] Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration2010
Author(s)
Ohki M, Ohki Y, Ishihara M, Nishida C, Tashiro Y, Akiyama H, Komiyama H, Lund LR, Nitta A, Yamada K, Zhu Z, Ogawa H, Yagita H, Okumura K, Nakauchi H, Werb Z, Heissig B, Hattori K
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Journal Title
Blood
Volume: 115
Pages: 4302-12
Peer Reviewed
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[Journal Article] Lnk regulates integrin alphaIIbbeta3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo2010
Author(s)
Takizawa H, Nishimura S, Takayama N, Oda A, Nishikii H, Morita Y, Kakinuma S, Yamazaki S, Okamura S, Tamura N, Goto S, Sawaguchi A, Manabe I, Takatsu K, Nakauchi H, Takaki S, Eto K
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Journal Title
J Clin Invest
Volume: 120
Pages: 179-90
Peer Reviewed
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[Journal Article] Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat52009
Author(s)
Xiao W, Hong H, Kawakami Y, Kato Y, Wu D, Yasudo H, Kimura A, Kubagawa H, Bertoli LF, Davis RS, Chau LA, Madrenas J, Hsia CC, Xenocostas A, Kipps TJ, Hennighausen L, Iwama A, Nakauchi H, Kawakami T
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Journal Title
Cancer Cell
Volume: 16
Pages: 161-71
Peer Reviewed
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[Journal Article] Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms2009
Author(s)
Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S
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Journal Title
Nature
Volume: 460
Pages: 904-8
Peer Reviewed
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