巨核球産生ニッチの可視化とニッチにおけるNotchシグナルの機能解析

• Project/Area Number: 22390191
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: 千葉 滋 筑波大学, 医学医療系, 教授 (60212049)
• Project Period (FY): 2010 – 2013
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 細胞・組織 / 巨核球 / ニッチ / Notch / CD42a / レポーター / トロンボポエチン

Research Abstract

骨髄巨核球は、巨核球と赤芽球の共通前駆細胞(MEP)に由来するとする説の他、諸説あるものの定説はない。GP1b(CD42)-V-IX複合体は、成熟骨髄巨核球と血小板で発現されていることはよく知られているが、造血前駆細胞における発現は知られてこなかった。報告者らの今回の研究ではまず、マウス骨髄でcommon myeloid progenitor(CMP)として同定される細胞(Lin-c-Kit+Sca1-CD34+CD16/32low)の3-6%において、GP1b(CD42)-V-IX複合体構成要素であるGP1bα(CD42b)が発現されていることを見いだした。このGP1bα陽性細胞は、培養すると成熟巨核球にのみ分化する能力を有していることを発見し、GP1bα+MegPと命名した。GP1bα+MegPは、MEPには由来せず、純度の高い造血幹細胞分画として知られるLin-c-Kit+Sca1+CD150+細胞に由来することが明らかになった。これらの発見は、造血幹細胞に直接由来する、巨核球分化の新たな経路の存在を示唆するものである。
一方、GP1bα+MegPは、Notchシグナル下流におけるもっとも重要な転写因子であるHes1を強く発現していることを見いだした。また、ヒト巨核球系細胞株であるUT7-TPOの成熟巨核球への分化が、Hes1のドミナント・ネガティブ変異体を導入することによって抑制された。
現在、Notchシグナルの中核分子であるRBP-JKノックアウトマウスなどを用いて、新たに見いだした巨核球分化経路におけるNotchシグナルの役割について解析を行なっている。

Research Products

• [Journal Article] Frequent pathway mutations of splicing machinery in myelodysplasia (2011)
  • Author(s): Kenichi Yoshida
  • Journal Title: Nature Volume: 478 Issue: 7367 Pages: 64-69
  • DOI: 10.1038/nature10496
  • Peer Reviewed
• [Journal Article] Notch-dependent and -independent regulation of mature B cell lineage fate and humoral immune response by the LRF transcription factor homodimer (2011)
  • Author(s): Nagisa Sakurai
  • Journal Title: Journal of Clinical Investigation Volume: 121 Issue: 7 Pages: 2583-2598
  • DOI: 10.1172/jci45682
  • Peer Reviewed
• [Journal Article] Brn-3b inhibits generation of amacrine cells by binding to and negatively regulating DLX1/2 in developing retina (2011)
  • Author(s): L.Feng
  • Journal Title: Neuroscience Volume: 195 Pages: 9-20
  • DOI: 10.1016/j.neuroscience.2011.08.015
  • Peer Reviewed
• [Journal Article] c-Maf plays a crucial role for the definitive erythropoiesis that accompanies erythroblastic island formation in the fetal liver (2011)
  • Author(s): 日下部学、長谷川和輝、濱田理人、中村恵弥、大住貴之、鈴木宏奈、工藤崇、内田和彦、二宮治彦、千葉滋、高橋智
  • Journal Title: Blood Volume: 118 Issue: 5 Pages: 1374-1385
  • DOI: 10.1182/blood-2010-08-300400
  • Peer Reviewed
• [Journal Article] Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria (2011)
  • Author(s): Yukinori Kozuma
  • Journal Title: British Journal of Haematology Volume: 152 Issue: 5 Pages: 631-639
  • DOI: 10.1111/j.1365-2141.2010.08505.x
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine (2011)
  • Author(s): Sakata-Yanagimoto M, Sakai T, Miyake Y, Saito TI, Maruyama H, Morishita Y, Nakagami- Yamaguchi E, Kumano K, Yagita H, Fukayama M, Ogawa S, Kurokawa M, Yasutomo K, Chiba S.
  • Journal Title: Blood Volume: 117 Pages: 128-134
  • NAID: 120007137632
  • Peer Reviewed
• [Journal Article] A nonradiation-containing, intermediate-dose methotrexate regimen for elderly patients with primary central nervous system lymphoma (2010)
  • Author(s): Taoka K, Okoshi Y, Sakamoto N, Takano S, Matsumura A, Hasegawa Y, Chiba S.
  • Journal Title: International Journal of Hematology Volume: 92 Pages: 617-623
  • NAID: 10027673973
  • Peer Reviewed
• [Journal Article] Treatment of central nervous system lymphoma in rats with intraventricular rituximab and serum (2010)
  • Author(s): Miyake Y, Okoshi Y, Machino T, Chiba S.
  • Journal Title: International Journal of Hematology Volume: 92 Pages: 474-480
  • NAID: 10027673501
  • Peer Reviewed
• [Journal Article] Difference in blood tacrolimus concentration between ACMIA and MEIA in samples with low haematocrit values (2010)
  • Author(s): Doki K, Homma M, Hori T, Tomita T, Hasegawa Y, Ito S, Fukunaga K, Kaneko M, Chiba S, Sumida T, Ohkohchi N, Kohda Y.
  • Journal Title: Journal of Pharmacy and Pharmacology Volume: 62 Pages: 1185-1188
  • Peer Reviewed
• [Journal Article] Notch2 signaling is required for potent anti-tumor immunity in vivo (2010)
  • Author(s): Sugimoto K, Maekawa Y, Kitamura A, Nishida J, Koyanagi A, Yagita H, Kojima H, Chiba S, Shimada M, Yasutomo K.
  • Journal Title: Journal of Immunology Volume: 184 Pages: 4673-4678
  • Peer Reviewed
• [Journal Article] Hesl immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia (2010)
  • Author(s): Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, Kumano K, HaradaY, Harada H, Kitaura J, Ogawa S, Kurokawa M, Kitamura T, Chiba S.
  • Journal Title: Blood Volume: 115 Pages: 2872-2881
  • Peer Reviewed
• [Presentation] Notch signaling as a mediator of myeloid differentiation and leukemic transformation (2010)
  • Author(s): Sakata-Yanagimoto M, Chiba S.
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: ポートピアホテル(神戸)
  • Year and Date: 2010-12-08
• [Presentation] Profiling of multiple gene mutations in myelodysplastic syndromes using high-throughput resequenceing combined with barcode labeling (2010)
  • Author(s): Nagata Y, Sanada M, Yoshida K, Nakaya T, Matsubara A, Obara N, Ishiyama N, Miyawaki S, Takita J, Chiba S, Shih L-Y, Koeffler HP, Ogawa S.
  • Organizer: The American Society of Hematology 52nd Annual Meeting
  • Place of Presentation: オーランド(米国フロリダ州)
  • Year and Date: 2010-12-06
• [Presentation] Whole exome analysis of myelodysplastic syndromes using next-generation resequencing technology (2010)
  • Author(s): Yoshida K, Sanada M, Nagata Y, Kawahata R, Kato M, Matsubara A, Takita J, Mori H, Ishiyama K, Ishikawa T, Miyawaki S, Obara N, Chiba S, Ogawa S.
  • Organizer: The American Society of Hematology 52nd Annual Meeting
  • Place of Presentation: オーランド(米国フロリダ州)
  • Year and Date: 2010-12-06
• [Presentation] Distinct roles of Notch signaling and Hes-1 on hematopoietic cell differentiation fate (2010)
  • Author(s): Chiba S.
  • Organizer: Notch and Stem Cells
  • Place of Presentation: アテネ(ギリシャ)
  • Year and Date: 2010-10-04
• [Presentation] Retrospective analysis of BCL2+DCBCL in the rituximab era : multi-center analysis (2010)
  • Author(s): Nishikii H, Nakamura N, Kondo Y, Kojima M, Takizawa J, Hasegawa Y, Okoshi Y, Suzukawa K, Yokoyama Y, Obara N, Sakata-Yanagimoto M, Noguchi M, Aoki M, Ando K, Chiba S.
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2010-09-25
• [Presentation] Outcome of methotrexate-based chemotherapy without whole-brain-irradiation in elderly PCNCL (2010)
  • Author(s): Taoka K, Okoshi Y, Suzukawa K, Takano S, Matsumura A, Hasewaga Y, Chiba S.
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2010-09-25
• [Book] Embryonic Stem Cells-Recent Advances in Pluripotent Stem Cell-Base Regene rative Medicine (2011)
  • Author(s): Craig S.Atwood
  • Total Pages: 410
  • Publisher: INTECH (Viena)
• [Book] 血液2011(Annual Review) (2011)
  • Author(s): 千葉滋(分担執筆)
  • Total Pages: 229
  • Publisher: 中外医学社
• [Book] 血液疾患最新の治療2011-2013 (2010)
  • Author(s): 千葉滋(分担執筆)
  • Total Pages: 408
  • Publisher: 南江堂
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/hematology/