The cell-surface modification enhances the engraftment of human CD34-positive cells into immunodeficient mice

• Project/Area Number: 19591250
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: KOBAYASHI Masao Hiroshima University, 大学院医歯薬学総合研究科, 教授 (00162016)
• Co-Investigator(Kenkyū-buntansha): KAJIUME Teruyuki 広島大学, 大学院・医歯薬学総合研究科, 助教 (40278924)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2007: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 造血幹細胞 / 細胞表面抗原 / 免疫不全マウス / 細胞接着因子 / 異種間移植 / 細胞接着蛋白 / 生着促進

Research Abstract

造血幹細胞移植においてドナー細胞の生着促進は臨床上重要な課題である。本研究ではヒト臍帯血由来造血細胞を純化後,生着促進に関係するケモカイン受容体の一つであるCXCR4の発現と免疫不全マウス(NOD/SCIDへの移植(静脈内輸注)を行った。2時間の無血清培養,好中球エラスターゼ処理を行うと造血幹細胞表面CXCR4の発現が有意に増加し,CXCR4のinhibitorであるAMD3100を培養に添加するとCXCR4の発現増加はほぼ完全に抑制された。培養後の造血細胞,AMD3100添加培養後の細胞,非培養細胞の移植の結果,16時間後のホーミング活性,8~10週後のマウス骨髄再構築能ともに細胞表面CXCR4 発現が増強された細胞群で有意なホーミング活性の増強とヒト細胞のマウス骨髄内の再構築能増加が認められた。臍帯血由来造血幹細胞は2時間の無血清培養により,自己複製能を維持しながら,CXCR4の発現増強を介して骨髄生着促進が認められることが明らかとなり,造血幹細胞表面の接着因子の発現を増強させることにより,少量の造血幹細胞でも骨髄生着が可能となることが示唆された。

Research Products

• [Journal Article] Ela2 mutations and clinical manifestations in familial congenital neutropenia (2009)
  • Author(s): Shiohara M, Shigemura T, Saito S, Tanaka M, Yanagisawa R, Sakashita K, Asada H, Ishii E, Koike K, Chin M, Kobayashi M, Koike K
  • Journal Title: Journal of Pediatric Hematology Oncology 31 Pages: 319-324
  • Peer Reviewed
• [Journal Article] 重症先天性好中球減少症の分子病態 (2009)
  • Author(s): 小林正夫 ,岡田賢 ,溝口洋子
  • Journal Title: 分子細胞治療 8 Pages: 110-116
• [Journal Article] Short-term culture of umbilical cord blood-derived CD34^+ cells enhances the engraftment into NOD/SCID mice through the increased expression of CXCR4 (2009)
  • Author(s): Ohno N, Kajiume T, Sera Y, Sato T, Kobayashi M
  • Journal Title: Stem Cells & Developments (in press) Pages: 0-0
  • Peer Reviewed
• [Journal Article] Deficiency of regulatory T cells in children with autoimmune neutropenia (2009)
  • Author(s): Nakamura K, Miki M, Karakawa S, Sato T, Kobayashi M
  • Journal Title: British Journal of Haematology (in press) Pages: 0-0
  • Peer Reviewed
• [Journal Article] Reciprocal expression of Bmi1 and Mel-18 is associated with the functioning of primitive hematopoietic cells (2009)
  • Author(s): Kajiume T, Ohno N, Sera Y, Kawahara Y, Yuge L, Kobayashi M
  • Journal Title: Experimental Hematology (in press) Pages: 0-0
  • Peer Reviewed
• [Journal Article] Cardiac infiltration in Early-Onset Sarcoidosis Associated with a Novel Heterozygous Mutation, G481D, in CARD15 (2009)
  • Author(s): Okada S, Konishi N, Tsumura M, Shirao K, Yasunga S, Sakai H, Nishikomori R, Takihara Y, Kobayashi M
  • Journal Title: Rheumatology (in press) Pages: 1093-1094
  • Peer Reviewed
• [Journal Article] Respiratory complications after haematopoietic stem cell transplantation in a patient with chronic granulomatous disease (2009)
  • Author(s): Hara K, Kajiume T, Kondo T, Sera Y, Kawaguchi H, Kobayashi M
  • Journal Title: Journal of Transfusion Medicine (in press) Pages: 0-0
  • Peer Reviewed
• [Journal Article] The mobility of Bach2 nuclear foci is regulated by SUMO-1 modification (2008)
  • Author(s): Kono K, Harano Y, Hoshino H, Kobayashi M, Bazett-Jones DP, Muto A, Igarashi K, Tashiro S
  • Journal Title: Experimental Cell Research 314(4) Pages: 903-13
  • Peer Reviewed
• [Journal Article] Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity (2008)
  • Author(s): Ohtsubo M, Yasunaga S, Ohno Y, Tsumura M, Okada S, Ishikawa N, Shirao K, Kikuchi A, Nishitani H, Kobayashi M, Takihara Y
  • Journal Title: Proc. Natl. Acad. Sci. USA 105(30) Pages: 10396-10401
  • Peer Reviewed
• [Journal Article] Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene (2008)
  • Author(s): Ishikawa N, Okada S, Miki M, Shirao K, Kihara H, Tsumura M, Nakamura K, Kawaguchi H, Ohtsubo M, Yasunaga S, Matsubara K, Sako M, Hara J, Shiohara M, Kojima S, Sato T, Takihara Y, Kobayashi M
  • Journal Title: Journal of Medical Genetics 45(12) Pages: 802-807
  • Peer Reviewed
• [Journal Article] Development of a new enzymatic diagnosis method for very-long-chain acyl-CoA dehydrogenase deficiency by detecting 2-hexadecenoyl-CoA production and its application in tandem mass spectrometry-based selective screening and newborn screening in Japan (2008)
  • Author(s): Tajima G, Sakura N, Shirao K, Okada S, Tsumura M, Nishimura Y, Ono H, Hata I, Naito E, Yamaguchi S, Shigematsu Y, Kobayashi M
  • Journal Title: Pediatric Research 64 Pages: 667-672
  • Peer Reviewed
• [Journal Article] 非結核性抗酸菌による多発性骨髄炎を呈したインターフェロンγ受容体1 異常症の2例 (2008)
  • Author(s): 岡田賢, 末永麻由美, 川口浩史, 小林正夫
  • Journal Title: 日本小児科学会雑誌 112 Pages: 1818-1825
  • NAID: 10024842949
  • Peer Reviewed
• [Journal Article] 好中球異常症 (2008)
  • Author(s): 小林正夫, 世羅康彦, 岡田賢
  • Journal Title: アレルギー・免疫 15 Pages: 1350-1360
• [Journal Article] 好中球異常による先天性免疫不全症 (2008)
  • Author(s): 岡田賢, 津村弥来, 小林正夫
  • Journal Title: 小児科臨床 61 Pages: 1791-1796
• [Journal Article] Polycomb-group complex 1 acts as an E3 ubiquitin ligase for Geminin to sustain hematopoietic stem cell activity. (2008)
  • Author(s): Ohtsubo M, Yasunaga s, Ohno Y, Kobayashi M, Takihara Y, et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 10396-10401
  • Peer Reviewed
• [Journal Article] Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. (2008)
  • Author(s): Ishikawa N, Okada s, Miki M, Takihara Y, Kobayashi M, et al
  • Journal Title: Journal of Medical Genetics 45 Pages: 802-807
  • Peer Reviewed
• [Journal Article] Short-term culture of umbilical cord blood-derived CD34^+ cells enhances the engraftment into NOD/SCID mice through the increased expression of CXCR4. (2008)
  • Author(s): Ohno N, Kajiume T, Sera Y, Satoh T, Kobayashi M
  • Journal Title: Stem Cells & Development (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-γ receptor 1 and has a dominant-negative effect on interferon-γ signal transduction. (2007)
  • Author(s): Okada S, Ishikawa N, Kobayashi M, et. al.
  • Journal Title: Journal of Human Genetics 44 Pages: 485-491
  • Peer Reviewed
• [Journal Article] Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency. (2007)
  • Author(s): Matsubara K, Imai K, Okada S, Kobayashi M, et. al.
  • Journal Title: Haematologica 92
  • Peer Reviewed
• [Journal Article] Floating culture promotes the maintenance of hematopoietic stem cells. (2007)
  • Author(s): Kajiume T, Yuge L, Kawahara Y, Kobayashi M, et. al.
  • Journal Title: FEBS Letters 581 Pages: 4645-4650
  • Peer Reviewed
• [Presentation] Reconstitution of Regulatory T Cells Involves in the Development of Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation (2008)
  • Author(s): Karakawa S, Nakamura K, Hara K, Mizoguchi Y, Miki M, Kawaguchi K, Sato T, Nishimura S, Kobayashi M
  • Organizer: American Society of Hematology, 50th Annual Meeting
  • Place of Presentation: San Francisco, CA, U.S.A.
  • Year and Date: 2008-12-07
• [Presentation] Short-Term Culture of Umbilical Cord Blood-Derived Stem Cells Enhances the Engraftment into NOD/SCID Mice through the Increased Expression of CXCR4. (2008)
  • Author(s): Ohno N, Kajiume T, Sera Y, Satoh T, Kobayashi M
  • Organizer: American Society of Hematology, 49th Annual Meeting.
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-12-07
• [Presentation] Novel Heterozygous Mutation 572insA in TACI Identified in a Patient with Selective IgA Deficiency (2008)
  • Author(s): Okada S, Kajiume T, Tsumura M, Shirao K, Ohno Y, Yasunaga S, Ohtsubo M, Sira MM, Kanegane H, Miyawaki T, Takihara Y, Kobayashi M
  • Organizer: American Society of Hematology, 50th Annual Meeting
  • Place of Presentation: San Francisco, CA, U.S.A.
  • Year and Date: 2008-12-06
• [Presentation] Short-Term Culture of Umbilical Cord Blood-Derived Stem Cells Enhances the Engraftment into NOD/SCID Mice through the Increased Expression of CXCR4 (2008)
  • Author(s): Ohno N, Kajiume T, Sera Y, Sato T, Kobayashi M
  • Organizer: American Society of Hematology, 50th Annual Meeting
  • Place of Presentation: San Francisco, CA, U.S.A.
  • Year and Date: 2008-12-06
• [Presentation] Association of Neurodevelopmental Abnormalities Is a Common Clinical Character in Japanese Patients with Severe Congenital Neutropenia Due to HAX1 Deficiency (2007)
  • Author(s): Okada S, Ishikawa N, Shirao K, Tsumura M, Sato T, Ohno Y, Yasunaga S, Ohtsubo M, Takihara Y, Kobayashi M
  • Organizer: American Society of Hematology, 49th Annual Meeting
  • Place of Presentation: Atlanta, GA, U.S.A.
  • Year and Date: 2007-12-10
• [Presentation] The Decrease of Regulatory T Cells through the Low Levels of FOXP3 Expression Mediated by NFAT1 in Infancy with Autoimmune Neutropenia (2007)
  • Author(s): Nakamura N, Miki M, Karakawa S, Onodera R, Kurita E, Hiraoka A, Sato T, Kobayashi M
  • Organizer: American Society of Hematology, 49th Annual Meeting
  • Place of Presentation: Atlanta, GA, U.S.A.
  • Year and Date: 2007-12-10
• [Presentation] Association of Neurodevelopmental Abnormalities Is a Common Clinical Character in Japanese Patients with Severe Congenital Neutropenia Due to HAX1 Deficiency. (2007)
  • Author(s): Okada S, Ishikawa N, Shirao K, Kobayashi M, et. al.
  • Organizer: American Society of Hematology, 49th Annual Meeting.
  • Place of Presentation: Atlanta, GA, USA
  • Year and Date: 2007-12-10
• [Presentation] The Expression of Polycomb Group Genes Products, Bmi1 and Mel-18, Regulate the Function of Murine Primitive Hematopoietic Cells (2007)
  • Author(s): Kajiume T, Takashi Sato T, Kobayashi M
  • Organizer: American Society of Hematology, 49th Annual Meeting
  • Place of Presentation: Atlanta, GA, U.S.A.
  • Year and Date: 2007-12-08
• [Book] 先天性好中球減少症の成因(Annual Review) (2008)
  • Author(s): 小林正夫, 岡田賢, 三木瑞香
  • Publisher: 中外医学社 東京
• [Book] Annual Review 血液 2008 (2008)
  • Author(s): 小林正夫, 岡田賢, 三木瑞香
  • Publisher: 中外医学社, 東京
• [Book] Annual Review血液2008 (2008)
  • Author(s): 小林正夫, 岡田 賢, 三木瑞香
  • Publisher: 中外医学社,東京