Molecular mechanism of the establishment and maintenance of the nteraction between hematopoietic stem cells and osteoblastic niche

• Project/Area Number: 18689024
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Keio University
• Principal Investigator: ARAI Fumio Keio University, 医学部, 講師 (90365403)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥28,210,000 (Direct Cost: ¥21,700,000、Indirect Cost: ¥6,510,000); Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000); Fiscal Year 2007: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2006: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: 造血幹細胞 / 幹細胞ニッチ / 骨芽細胞 / ニッチ / N-cadherin / 間葉系前駆細胞 / 骨芽細胞性ニッチ / ニッチ複合体 / SP(sde-population) / 活性酸素 / 血管性ニッチ / 静止期造血幹細胞 / VE-cadherin / β-catenin

Research Abstract

造血幹細胞の未分化性維持には骨芽細胞性ニッチとの相互作用が重要であり、その制御にMpl/Thrombopoietin、N-cadherinが重要な機能を果たしていることを同定した。また、骨芽細胞性ニッチは分化段階の異なる複数の細胞により構成されることを見いだした。さらに、ニッチ分子の機能阻害により、幹細胞がニッチから離れ、活性化されることがわかった。これは、ニッチ分子の機能修飾により、造血幹細胞の動態を制御できることを示しており、今後、低侵襲条件での幹細胞移植をはじめとした再生医療に応用できると考えられた。

Research Products

• [Journal Article] Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice. (2009)
  • Author(s): Shima H, Takubo K, Iwasaki H, Yoshihara H, Gomei Y, Hosokawa K, Arai F, Takahashi T, Suda T.
  • Journal Title: Biochem Biophys Res Commun 378 Pages: 467-472
  • Peer Reviewed
• [Journal Article] Angiopoietins contribute to lung development by regulating pulmonary vascular network formation. (2009)
  • Author(s): Hato T, Kimura Y, Morisada T, Koh GY, Miyata K, Tabata M, Kadomatsu T, Endo M, Urano T, Arai F, et al.
  • Journal Title: Biochem Biophys Res Commun 381 Pages: 218-223
  • Peer Reviewed
• [Journal Article] Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice (2009)
  • Author(s): Shima H
  • Journal Title: Biochem Biophys Res Commun 378 Pages: 467-472
  • Peer Reviewed
• [Journal Article] Angiopoietins contribute to lung development by regulating pulmonary vascular network formation (2009)
  • Author(s): Hato T
  • Journal Title: Biochem Biophys Res Commun 381 Pages: 218-223
  • Peer Reviewed
• [Journal Article] Wnt signaling in the niche (2009)
  • Author(s): Suda T
  • Journal Title: Cell 132 Pages: 729-730
• [Journal Article] Niche Regulation of Hematopoietic Stem Cells in the Endosteum. The Role of Thrombopoietin/Mpl Signaling in the Maintenance of Quiescent Hematopoietic Stem Cells (2009)
  • Author(s): Arai F
  • Journal Title: Ann N Y Acad Sci (in press)
  • Peer Reviewed
• [Journal Article] Wnt signaling in the niche. (2008)
  • Author(s): Suda T, Arai F.
  • Journal Title: Cell 132 Pages: 729-730
• [Journal Article] dentification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity. (2008)
  • Author(s): Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, Hirao A.
  • Journal Title: Stem Cells. 26 Pages: 3237-3246
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical failsafe against premature loss of hematopoietic stem cells and development of T-ALL. (2008)
  • Author(s): Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, Mashimo Y, Oguro H, Nitta E, Ito K, Miyamoto K, Yoshiwara H, Hosokawa K, Nagamatsu G, Nakamura Y, Gomei Y, Iwasaki H, Shima H, Hayashi Y, Matsuzaki Y, Nakayama K, Ikeda Y, Hata A, Chiba S, Nakayama KI, Suda T.
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] Stem Cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest. (2008)
  • Author(s): Takubo K, Ohmura M, Azuma M, Nagamatsu G, Yamada W, Arai F, Hirao A, Suda T.
  • Journal Title: Cell Stem Cell. 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] stem Cell defects in ATM-deficient undifferentiated spermatogonia through DNA damage-induced cell cycle arrest (2008)
  • Author(s): Takubo K
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical failsafe against premature loss of hematopoietic stem cells and development of T-ALL (2008)
  • Author(s): Matsuoka S
  • Journal Title: Genes Dev 22 Pages: 986-991
  • Peer Reviewed
• [Journal Article] Identification of stem cells during prepubertal spermatogenesis viamonitoring of nucleostemin promoter activity (2008)
  • Author(s): Ohmura M
  • Journal Title: Stem Cells 26 Pages: 3237-3246
  • Peer Reviewed
• [Journal Article] ATM-deficient undifferentiated speraiatogonia through DNA damage-induced cell cycle arrest. (2008)
  • Author(s): Takubo K
  • Journal Title: Cell Stem Cell 2 Pages: 170-182
  • Peer Reviewed
• [Journal Article] Fbxw7 acts as a critical failsafe against premature loss of hematopoietic stem cells and development of T-ALL (2008)
  • Author(s): Matsuoka S
  • Journal Title: Genes Dev 印刷中
  • Peer Reviewed
• [Journal Article] Wnt signaling in the niche. (2008)
  • Author(s): Suda T
  • Journal Title: Cell 132 Pages: 729-730
• [Journal Article] Thrombopoietin/Mpl signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. (2007)
  • Author(s): Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K, Miyazaki H, Takahashi T, Suda T.
  • Journal Title: Cell Stem Cell. 363 Pages: 685-697
  • Peer Reviewed
• [Journal Article] Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. (2007)
  • Author(s): Hosokawa K, Arai F, Yoshihara H, Nakamura Y, Gomei Y, Iwasaki H, Miyamoto K, Shima H, Ito K, Suda T.
  • Journal Title: Biochem Biophys Res Commun. 363 Pages: 578-583
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of hematopoietic stem cell pool. (2007)
  • Author(s): Miyamoto K, Araki K, 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.
  • Journal Title: Cell Stem Cell. 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Regulation of reactive oxygen species by Atm is essential for proper response to DNA double strand breaks in lymphocytes. (2007)
  • Author(s): Ito K, Takubo K, Arai F, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa K, Ikeda Y, Mak TW, Suda T, Hirao A.
  • Journal Title: J. Immunol. 178 Pages: 103-110
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. (2007)
  • Author(s): Ninomiya M, Abe A, Katsumi A, Xu J, Ito M, Arai F, Suda T, Ito M, Kiyoi H, Kinoshita T, Naoe T.
  • Journal Title: Leukemia. 21(1) Pages: 136-142
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivoin immunodeficient mice (2007)
  • Author(s): Ninomiya M
  • Journal Title: Leukemia 21 Pages: 136-142
  • Peer Reviewed
• [Journal Article] Regulation of reactive oxygen species by Atm is essential for proper response to DNA double strand breaks in lymphocytes. (2007)
  • Author(s): Ito K
  • Journal Title: J. Immunol. 178 Pages: 103-110
  • Peer Reviewed
• [Journal Article] Foxo3a is essential for maintenance of hematopoietic stem cell pool. (2007)
  • Author(s): Miyamoto K
  • Journal Title: Cell Stem Cell 1 Pages: 101-112
  • Peer Reviewed
• [Journal Article] Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction. (2007)
  • Author(s): Hosokawa K
  • Journal Title: Biochem Biophys Res Commun 363 Pages: 578-583
  • Peer Reviewed
• [Journal Article] Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche (2007)
  • Author(s): Yoshihara H
  • Journal Title: Cell Stem Cell 1 Pages: 685-697
  • Peer Reviewed
• [Journal Article] Role of stem cell niche in the maintenance of hematopoietic stem cells. (2007)
  • Author(s): Arai F
  • Journal Title: Inflammation and Regeneration 27 Pages: 117-123
  • NAID: 10019482602
• [Journal Article] Regulation of hematopoietic stem cells in the osteoblastic niche (2007)
  • Author(s): Arai F
  • Journal Title: Adv Exp Med Biol 602 Pages: 61-67
  • NAID: 40015350814
  • Peer Reviewed
• [Journal Article] Maintenance of quiescent hematopoietic stem cells in the osteoblasticniche (2007)
  • Author(s): Arai F
  • Journal Title: Ann N Y Acad Sci 1106 Pages: 41-53
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. (2007)
  • Author(s): Manabu Ninomiya
  • Journal Title: Leukemia 21・1 Pages: 136-142
• [Journal Article] Regulation of reactive oxygen species by Atm is essential for proper response to DNA double strand breaks in lymphocytes. (2007)
  • Author(s): Keisuke Ito
  • Journal Title: J Immunol 178・1 Pages: 103-110
• [Journal Article] Foxo3a is essential for maintenance of hematopoietic stem cell pool. (2007)
  • Author(s): Kana Miyamoto
  • Journal Title: Cell Stem Cell (in press)
• [Journal Article] Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. (2007)
  • Author(s): Fumio Arai
  • Journal Title: Ann N Y Acad Sci (in press)
• [Journal Article] Regulation of hematopoietic stem cells in the osteoblastic niche. (2007)
  • Author(s): Fumio Arai
  • Journal Title: Osteoimmunology : Interactions of the Immune and Skeletal System (in press)
  • NAID: 40015350814
• [Journal Article] Premeiotic germ cell defect in seminiferous tubules of Atm-null testis. (2006)
  • Author(s): Takubo K, Hirao A, Ohmura M, Azuma M, Arai F, Nagamatsu G, Suda T.
  • Journal Title: Biochem Biophys Res Commun. 351 Pages: 993-998
  • Peer Reviewed
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y and Suda T.
  • Journal Title: Nat Med, 12 Pages: 446-451
  • Peer Reviewed
• [Journal Article] Regulation of hematopoietic stem cell and its interaction with stem cell niche. (2006)
  • Author(s): Arai F.
  • Journal Title: J Oral Biosci 48 Pages: 22-29
  • NAID: 120006665069
  • Peer Reviewed
• [Journal Article] Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. (2006)
  • Author(s): Keisuke Ito
  • Journal Title: Nat Med 12・4 Pages: 446-451
• [Journal Article] Premeiotic germ cell defect in seminiferous tubules of Atm-null testis. (2006)
  • Author(s): Keiyo Takubo
  • Journal Title: Biochem Biophys Res Commun 351・4 Pages: 993-998
• [Journal Article] Cadherin-based adhesion is a otential target for niche nipulation to protect matopoietic stem cells in adult bone marrow
  • Author(s): Hsokawa K, Arai F, Yoshihara H, wasaki H, Hembree M, Yin T, akamura N, Gomei Y, Takubo K, hiama H, Matsuoka S, Li L, Suda T.
  • Journal Title: Cell Stem Cell (in press)
  • Peer Reviewed
• [Journal Article] IRF-2 protects quiescent HSCs from type-I interferon-dependent exhaustion.
  • Author(s): Sato T, Onai N, Yoshihara H, Arai F ,Suda T, Ohteki T.
  • Journal Title: Nat Med (in press)
  • Peer Reviewed
• [Presentation] Hematopoietic stem cell niche (2009)
  • Author(s): Arai F
  • Organizer: The 5th General Assembly with Asian Symposium-2009
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2009-02-14
• [Presentation] Hematopoietic stem cell niche (2009)
  • Author(s): Arai F.
  • Organizer: The 5th General Assembly with Asian Symposium-2009
  • Place of Presentation: Kobe, Japan.
• [Presentation] Niche regulation of hematopoietic stem cells in the endosteum (2008)
  • Author(s): Arai F
  • Organizer: International Conference and Workshop. Hematopoietic Stem Cells VII
  • Place of Presentation: Meersburg, Germany
  • Year and Date: 2008-09-18
• [Presentation] 幹細胞のニッチ制御 (2008)
  • Author(s): 新井 文用
  • Organizer: 第7回日本再生医療学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-03-14
• [Presentation] Niche regulation of hematopoietic stem cells in the endosteum. (2008)
  • Author(s): Arai F.
  • Organizer: International Conference and Workshop. Hematopoietic Stem Cells VII.
  • Place of Presentation: Meersburg, Germany
• [Presentation] 造血幹細胞のニッチ制御 (2007)
  • Author(s): 新井 文用
  • Organizer: 第49回歯科基礎医学会学術大会・総会
  • Place of Presentation: 北海道大学
  • Year and Date: 2007-08-31
• [Presentation] Regulation of the hematopoietic stem cell and its interaction with the osteoblastic niche (2007)
  • Author(s): Arai F
  • Organizer: Gordon Research Conference, Bone & Teeth
  • Place of Presentation: University of New England, Biddeford, ME
  • Year and Date: 2007-07-17
• [Presentation] Interaction of N-cadherin with beta-catenin is involved in the maintenance of hematopoietic stem cell quiescence in the osteoblastic niche. (2007)
  • Author(s): Arai F
  • Organizer: 5th ISSCR Annual Meeting
  • Place of Presentation: Cairns, Queensland,Australia
  • Year and Date: 2007-06-19
• [Presentation] 骨髄微小環境と造血幹細胞制御 (2007)
  • Author(s): 新井 文用
  • Organizer: 第61回日本口腔科学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2007-04-20
• [Presentation] Regulation of the hematopoietic stem cell and its interaction with the osteoblastic niche. (2007)
  • Author(s): Arai F.
  • Organizer: Gordon Research Conference, Bone & Teeth
  • Place of Presentation: University of New England, Biddeford, ME, USA
• [Presentation] Interaction of N-cadherin with b-catenin is involved in then maintenance of hematopoietic stem cell quiescence in the osteoblastic niche. (2007)
  • Author(s): Arai F, Hosokawa K, Yoshihara H, Takubo K, Matsuoka S, Miyamoto K, Nakamura Y, Gomei Y, Suda T.
  • Organizer: 5th International Society for Stem Cell Research Annual Meeting
  • Place of Presentation: Cairns, Australia.
• [Presentation] Regulation of hematopoietic stem cells by the niche. (2006)
  • Author(s): Arai F.
  • Organizer: Stem Cell Biology and Regenerativec Medicine-from Bench to Bedside.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2006-01-14
• [Presentation] Maintenance of stem cells in the niche. International Conference and Workshop. (2006)
  • Author(s): Arai F.
  • Organizer: Hematopoietic Stem Cells VI.
  • Place of Presentation: Tubingen, Germany.
• [Presentation] Regulation of hematopoietic stem cells in the osteoblastic niche. (2006)
  • Author(s): Arai F.
  • Organizer: 1st International Conference on Osteoimmunology : Interaction of the Immune and Skeletal Systems.
  • Place of Presentation: Crete, Greece.
• [Presentation] Regulation of hematopoietic stem cell and its interaction with stem cell niche. (2006)
  • Author(s): Arai F.
  • Organizer: Hiroshima conference on education and science in dentistry, 2006.
  • Place of Presentation: Hiroshima, Japan
• [Book] Stem Book (2009)
  • Author(s): Arai F
  • Publisher: The Stem Cell Research Community, StemBook(in press)
• [Book] Regulation of hematopoietic stem cells in the osteoblastic niche. Osteoimmunology : Interactions of the Immune and Skeletal System (Choi Y, edited) (2007)
  • Author(s): Arai F, Suda T.
  • Publisher: Adv Exp Med Biol.
• [Book] Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Hematopoietic Stem Cells VI. (2007)
  • Author(s): Arai F, Suda T.
  • Publisher: Ann N Y Acad Sci
• [Book] Osteo immunology: Interactions of the Immune and Skeletal System (2007)
  • Author(s): Arai F
  • Publisher: Springer
• [Book] Landes Bioscience/Eurekah.com (2006)
  • Author(s): Arai F, Suda T.
  • Publisher: Endothelial and hematopoietic cells in the intraembryonic compartment. In Hematopoietic Stem Cell Development. (edited by Godin I and Cumano A)
• [Remarks]
  • URL: http://web.Sc.itc.keio.ac.jp/celldiff/index.html