Identification of niche signal prescribing hibernation of hematopoietic stem cell

2008 Fiscal Year Final Research Report

• Project/Area Number: 19209036
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: NAKAUCHI Hiromitsu The University of Tokyo, 医科学研究所, 教授 (40175485)
• Co-Investigator(Kenkyū-buntansha): OTSU Makoto 東京大学, 医科学研究所, 助教 (30361330)
• Project Period (FY): 2007 – 2008
• Keywords: 造血幹細胞 / リッピドラフト / 冬眠 / ニッチ / FOXO

Research Abstract

(200字程度、難解な専門用語は避けること)骨髄ニッチに存在する造血幹細胞にはLipid raft clustering(LRC)がなく、骨髄中の前駆細胞や骨髄から取り出してきてサイトカイン刺激した造血幹細胞にはLRC が存在するという事実から骨髄ニッチにはLRC 形成を阻害する因子(シグナル)があるのではないかと考えた.この仮説のもと、ニッチシグナル分子と考えられている分子を対象として、サイトカイン刺激においてもLRC を阻害する分子をスクリーニングした.その結果、TGF-beta がLRC を阻害することを明らかにし、骨髄ニッチシグナルの一つの候補としてTGF-beta を同定した

Research Products

• [Journal Article] Insights intosignaling and function of hematopoieticstem cells at the single-cell leve (2009)
  • Author(s): Yamazaki S, Nakauchi H
  • Journal Title: CurrOpin Hematol (in press).
• [Journal Article] Analyses of cell surface molecules onhepatic stem/progenitor cells in mouse fetalliver (2009)
  • Author(s): Kakinuma S, Ohta H, Kamiya A, YamazakiY, Oikawa T, Okada K, Nakauchi H.
  • Journal Title: J Hepatol. (in press)
• [Journal Article] The actin polymerization regulatorWAVE2 is required for early bone marrowrepopulation by hematopoietic stem cells (2009)
  • Author(s): Ogaeri T, Eto K, Otsu M, Ema H, NakauchiH
  • Journal Title: Stem Cells 27 Pages: 1120-1129
• [Journal Article] Stepwise development of hematopoieticstem cells from embryonic stem cells (2009)
  • Author(s): Matsumoto K, Isagawa T, Nishimura T, Ogaeri T, Eto K, Miyazaki S, Miyazaki J, Aburatani H, Nakauchi H, Ema H
  • Journal Title: PLoS ONE 4820
• [Journal Article] cell growth control using hapten-specificantibody/interleukin-2 receptor chimera (2009)
  • Author(s): Onodera M, Nakauchi H, Nagamune T. T
  • Journal Title: Cytokine(in press)
• [Journal Article] Hepatic stem/progenitor cells and stem-celltransplantation for the treatment of liverdisease (2009)
  • Author(s): Kakinuma S, Nakauchi H, Watanabe M
  • Journal Title: J Gastroenterol 44 Pages: 167-72
• [Journal Article] rapid and efficient strategy to generateallele-specific anti-HLA monoclonalantibodies (2009)
  • Author(s): Yamazaki S, Suzuki N, Saito T, Ishii Y,Takiguchi M, Nakauchi H, Watanabe N. A
  • Journal Title: J Immunol Methods 343 Pages: 56-60
• [Journal Article] Sall4 regulates cell fate decision in fetalhepatic stem/progenitor cells (2009)
  • Author(s): Oikawa T, Kamiya A, Kakinuma S, ZeniyaM, Nishinakamura R, Tajiri H, Nakauchi H
  • Journal Title: Gastroenterology 136 Pages: 1000-11
• [Journal Article] Transcriptional profiling of hematopoieticstem cells by high-throughput sequencing (2009)
  • Author(s): Yashiro Y, Bannai H, Minowa T, Yabiku T, Miyano S, Osawa M, Iwama A, Nakauchi H
  • Journal Title: Int J Hematol 89 Pages: 24-33
• [Journal Article] TGF-b induceshibernation of hematopoietic stem cells inthe bone marrow niche (2009)
  • Author(s): Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H
  • Journal Title: Blood 113 Pages: 1250-1256
• [Journal Article] guidelines underscore major principles forresponsible translational stem cell research. (2008)
  • Author(s): Hyun I, Lindvall O, Ahrlund-Richter L Cattaneo E, Cavazzana-Calvo M, Cossu G, De Luca M, Fox IJ, Gerstle C, GoldsteinRA, Hermeren G, High KA, Kim HO, LeeHP, Levy-Lahad E, Li L, Lo B, MarshakDR, McNab A, Munsie M, Nakauchi H, Rao M, Rooke HM, Valles CS, Srivastava A, Sugarman J, Taylor PL, Veiga A, Wong AL, Zoloth L, Daley GQ. New ISSCR
  • Journal Title: Cell Stem Cell. 3 Pages: 607-9
• [Journal Article] Flow cytometric isolation and clonalidentification of self-renewing bipotenthepatic progenitor cells in adult mouse liver (2008)
  • Author(s): Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H, Nakauchi H, Taniguchi H
  • Journal Title: Hepatology 48 Pages: 1964-78
• [Journal Article] Thepolycomb gene product BMI1 contributesto the maintenance of tumor-initiating sidepopulation cells in hepatocellular carcinoma (2008)
  • Author(s): Chiba T, Miyagi S, Saraya A, Aoki R, SekiA, Morita Y, Yonemitsu Y, Yokosuka O, Taniguchi H, Nakauchi H, Iwama A.
  • Journal Title: Cancer Res 68 Pages: 7742-9
• [Journal Article] Generation of functional erythrocytes fromhuman embryonic stem cell-deriveddefinitive hematopoiesis (2008)
  • Author(s): Ma F, Ebihara Y, Umeda K, Sakai H, Hanada S, Zhang H, Zaike Y, Tsuchida E, Nakahata T, Nakauchi H, Tsuji K
  • Journal Title: Proc Natl AcadSci U S A 105 Pages: 13087-92
• [Journal Article] Prospero-related homeobox 1 and liverreceptor homolog 1 coordinately regulatelong-term proliferation of murine fetalhepatoblasts (2008)
  • Author(s): Kamiya A, Kakinuma S, Onodera M, Miyajima A, Nakauchi H
  • Journal Title: Hepatology 48 Pages: 252-64
• [Journal Article] Metalloproteinaseregulation improves in vitro generation ofefficacious platelets from mouse embryonicstem cells (2008)
  • Author(s): Nishikii H, Eto K, Tamura N, Hattori1 K,Heissig B, Kanaji T, Sawaguchi A, Goto S,Ware J, Nakauchi H
  • Journal Title: J Exp Med 205 Pages: 1917-27
• [Journal Article] Recipient-derived cells after cord bloodtransplantation : dynamics elucidated bymulticolor FACS, reflecting graft failureand relapse (2008)
  • Author(s): Watanabe N, Takahashi S, Ishige M, Ishii Y, Ooi J, Tomonari A, Tsukada N, Konuma T, Kato S, Sato A, Tojo A, Nakauchi H
  • Journal Title: Biol Blood Marrow Transplant 14 Pages: 693-701
• [Journal Article] Generation of functional platelets fromhuman embryonic stem cells in vitro viaES-sacs, VEGF-promoted structures thatconcentrate hematopoietic progenitors (2008)
  • Author(s): Takayama N, Nishikii H, Usui J, Tsukui H, Sawaguchi A, Hiroyama T, Eto K, Nakauchi H
  • Journal Title: Blood 1 Pages: 5298-306
• [Journal Article] Growth and maturation of megakaryocytes is regulatedby Lnk/Sh2b3 adaptor protein throughcrosstalk between cytokine- andintegrin-mediated signals (2008)
  • Author(s): Takizawa H, Eto K, Yoshikawa A, NakauchiH, Takatsu K, Takaki S.
  • Journal Title: Exp Hematol 36 Pages: 897-906
• [Journal Article] Interleukin-27 directlyinduces differentiation in hematopoieticstem cells (2008)
  • Author(s): Seita J, Asakawa M, Ooehara J, TakayanagiSI, Morita Y, Watanabe N, Fujita K, KudoM, Mizuguchi J, Ema H, Nakauchi H, Yoshimoto Y
  • Journal Title: Blood 111 Pages: 1903-12
• [Journal Article] An immunotherapy approachwith dendritic cells genetically modified toexpress the tumor-associated antigen (2008)
  • Author(s): Nabekura T, Nagasawa T, Nakauchi H, Onodera M
  • Journal Title: HER2.Cancer Immunol Immunother 57 Pages: 611-22
• [Journal Article] The Plasminogen Fibrinolytic Pathway IsRequired for Hematopoietic Regeneration (2007)
  • Author(s): Heissig B, Lund LR, Akiyama H, Ohki M, Morita Y, Romer J, Nakauchi H, OkumuraK, Ogawa H, Werb Z, Dano K, Hattori K
  • Journal Title: Cell Stem Cell 1 Pages: 658-70
• [Journal Article] Foxo3a is essential formaintenance of the hematopoietic stem cellpool (2007)
  • Author(s): 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
  • Journal Title: Cell Stem Cell 1 Pages: 101-12
• [Journal Article] Enhancedself-renewal capability in hepaticstem/progenitor cells drives cancerinitiation (2007)
  • Author(s): Chiba T, Zheng YW, Kita K, Yokosuka O,Saisho H, Onodera M, Miyoshi H, NakanoM, Zen Y, Nakanuma Y, Nakauchi H, Iwama A, Taniguchi H.
  • Journal Title: Gastroenterology 137 Pages: 937-50
• [Journal Article] Cytokine signaling, lipid raft clustering, and HSC hibernation (2007)
  • Author(s): Yamazaki S, Iwama A, Morita Y, Eto K,Ema H, Nakauchi H
  • Journal Title: Ann N Y Acad Sci 1106 Pages: 54-63
• [Journal Article] De novo DNAmethyltransferase is essential forself-renewal, but not for differentiation (2007)
  • Author(s): Eto K, Nishikii H, Ogaeri T, Suetsugu S,Kamiya A, Kobayashi T, Yamazaki D, OdaA, Takenawa T, Nakauchi H
  • Journal Title: Blood 110 Pages: 3637-47
• [Journal Article] De novo DNAmethyltransferase is essential forself-renewal, but not for differentiation inhematopoietic stem cells (2007)
  • Author(s): Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H
  • Journal Title: J Exp Med 204 Pages: 715-22
• [Journal Article] Unique composition ofpolycomb repressive complex 1 inhematopoietic stem cells (2007)
  • Author(s): Kato Y, Koseki H, Vidal M, Nakauchi H, Iwama A
  • Journal Title: Int J Hematol 85 Pages: 179-81
• [Journal Article] Lnknegatively regulates self-renewal ofhematopoietic stem cells by modifyingthrombopoietin-mediated signaltransduction (2007)
  • Author(s): Seita, J., Ema, H., Ooehara, J., Yamazaki, S.,Tadokoro, Y., Yamazaki, A., Eto, K., Takaki,S., Takatsu, K., and Nakauchi H
  • Journal Title: Proc Natl Acad Sci USA 104 Pages: 2349-54
• [Journal Article] Stable Transgene Expression in MiceGenerated from Retrovirally TransducedEmbryonic Stem (2007)
  • Author(s): Hamanaka S, Nabekura T, Otsu M, YoshidaH, Nagata M, Usui J, Takahashi S,Nagasawa T, Nakauchi H, Onodera M
  • Journal Title: Cells. Mol Ther 15 Pages: 560-5
• [Journal Article] Iawama A. Bmi1 cooperates withDnmt1-assciated protein 1 in gene silencing (2007)
  • Author(s): Negishi M, Saraya A, Miyagi S, Nagao K,Inagaki Y, Nishikawa M, Tajima S, KosekiH, Tsuda H, Takasaki Y, Nakauchi H
  • Journal Title: Biochem Biophys Res Commun 353 Pages: 992-8
• [Journal Article] Definitive proof fordirect reprogramming of hematopoieticcells to pluripotency
  • Author(s): Okabe M, Otsu M, Ahn DH, Kobayashi T, Wakiyama Y, Morita Y, Onodera M, Eto K, Ema H, Nakauchi H
  • Journal Title: Blood. (in press)
• [Presentation] HSC Hierarchy of hematopoietic stem cells (2009)
  • Author(s): Nakauchi H.
  • Organizer: USA-JapanCooperative Cancer Workshop "Stem Cells inNormal and Malignant Hematopoiesis(Invited Speaker)
  • Place of Presentation: Hawaii, USA
  • Year and Date: 20090527-29
• [Presentation] Symposium on MolecularMechanisms of Adult Stem cell Aging (2009)
  • Author(s): Nakauchi H
  • Organizer: Heterogeneity and a hierarchy within themost primitive hematopoietic stem cellcompartment
  • Place of Presentation: Reisensburg ,Germany
  • Year and Date: 20090521-24
• [Presentation] Analysis of Signaling Eventsin hematopetic Stem Cells, a Vary rarePopulation in the Bone Marrow (2009)
  • Author(s): Nakauchi H
  • Organizer: 34^<th> LorneConference on Protein Structure and Function (Invited Speaker)
  • Place of Presentation: Eskine Mantra Resort,Lorne Australia
  • Year and Date: 20090208-12
• [Presentation] Molecular reguration ofhematopoetic stemcell self-renewal anddormancy (2009)
  • Author(s): Nakauchi H
  • Organizer: Internatinal PhD Program in Immuology, CellBiology and Biochemistry2008-2009 Lecture Course(Invited Speaker)
  • Place of Presentation: Switzerland
  • Year and Date: 2009-05-28
• [Presentation] Generation of functionalplatelets from human pluripotent stem cells invitro (2008)
  • Author(s): Nakauchi H
  • Organizer: 2008 TREMIS-AP Chapter Meeting (Invited Speaker)
  • Place of Presentation: Taipei
  • Year and Date: 20081106-08
• [Presentation] Hibernation of hematopoieticstem sells in the bone marrow niche (2008)
  • Author(s): Nakauchi H
  • Organizer: The9th International Congress on Cell Biology(ICCB 2008) & The 20th Annual Conferenceof the Korean Society for Molecular andCellular Biology (Invited Speaker)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20081007-10
• [Presentation] Silencing : Hibernation ofhematopoietic stem cells in the bone marrowniche (2008)
  • Author(s): Nakauchi H
  • Organizer: Meeting of Barsinghausen
  • Place of Presentation: Germany
  • Year and Date: 20080901-05
• [Presentation] TGF-βas a Candidate BoneMarrow Niche Signal to induce Hematopoietic Stem Cell Hibernation (2008)
  • Author(s): Nakauchi H
  • Organizer: ISEH2008 Meeting Invited Speaker
  • Place of Presentation: Boston, U.S.A
  • Year and Date: 20080710-12
• [Presentation] Hibernation of HematopoieticStem Cells in the Bone Marrow Niche (2008)
  • Author(s): Nakauchi H
  • Organizer: 13thCongress of the European HematologyAssociation Invited Speaker
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 20080612-15
• [Presentation] Cytokine Signals Modulated ViaLipid Rafts Induce Hibernation inHematopoietic Stem Cells (2008)
  • Author(s): Nakauchi H
  • Organizer: InternationalSociety for Stem Cell Research 6th AnnualMeeting (ISSCR)Invited Speaker
  • Place of Presentation: Philadelphia, U.S.A.
  • Year and Date: 20080611-14
• [Presentation] TGF-βas a candidate bonemarrow niche signal to induce hematopoieticstem cell hibernation (2008)
  • Author(s): Nakauchi H
  • Organizer: The 5th NikkoInternational Symposium 2008 Invited Speaker
  • Place of Presentation: Shimotsuke, Tochigi Japan
  • Year and Date: 2008-10-25
• [Patent(Industrial Property Rights)] GPIbα+GPV+GPVI+血小板のインビトロ調製法 (2009)
  • Inventor(s): 中内啓光、江藤浩之、錦井秀和、高山直也
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Number: 25B082001-1
  • Filing Date: 2009-03-27
• [Patent(Industrial Property Rights)] iPS 細胞からの血小板の調製方法 (2009)
  • Inventor(s): 中内啓光、江藤浩之、錦井秀和、高山直也、山中伸弥、高橋和利
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Number: 25B083003-
  • Filing Date: 2009-04-01
• [Patent(Industrial Property Rights)] ウイルス産生細胞 (2009)
  • Inventor(s): 中内啓光、江藤浩之、大津真、高山直也
  • Industrial Property Rights Holder: 国立大学法人 東京大学
  • Industrial Property Number: 25B093006-1・25B093005-1
  • Filing Date: 2009-05-15
• [Patent(Industrial Property Rights)] 遺伝子改変による致死性表現型を持つ動物の繁殖用ファウンダー動物作製法 (2008)
  • Inventor(s): 中内啓光, 小林俊寛
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 特願2008-042243
  • Filing Date: 2008-02-22
• [Patent(Industrial Property Rights)] GPIbα+血小板のインビトロ調製法 (2008)
  • Inventor(s): 中内啓光、江藤浩之、錦井秀和、高山直也
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: 特願2008-085204
  • Filing Date: 2008-03-28
• [Patent(Industrial Property Rights)] iPS 細胞からの血小板の調製方法 (2008)
  • Inventor(s): 中内啓光、江藤浩之、錦井秀和、高山直也、山中伸弥(京大)、高橋和利(京大)
  • Industrial Property Rights Holder: 国立大学法人東京大学、国立大学法人京都大学
  • Industrial Property Number: 特願2008-094584
  • Filing Date: 2008-04-01
• [Patent(Industrial Property Rights)] ES 細胞からの造血前駆細胞を内包する構造物、及び該構造物を用いた血球細胞の調整方法 (2007)
  • Inventor(s): 中内啓光、江藤浩之、高山直也, 錦井秀和, 津久井弘子
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Number: PCT/JP2007/001081
  • Filing Date: 2007-10-04