2003 年度実績報告書

造血幹細胞の増殖・分化とその異常に関する研究

研究課題

研究課題/領域番号	12215067
研究機関	京都大学
研究代表者	中畑龍俊京都大学, 医学研究科, 教授 (20110744)
研究分担者	足立壮一京都大学, 医学研究科, 助手 (10273450) 依藤享京都大学, 医学研究科, 講師 (60220779)
キーワード	白血病 / 造血幹細胞 / サイトカイン / G-CSFR / Kostmann症候群 / 発生 / 分化 / 遺伝子クローン
研究概要	本研究ではマウス胎生期における造血幹細胞の発生とその異常を明らかにするとともに、様々な方法を用いてヒト造血幹細胞の性状・増殖・分化過程を明らかにすることを一つの目的としている。さらに、サイトカイン受容体の異常と白血病発症との因果関係、白血病発症の分子機構が明らかにすることを目的に行い以下の成果が得られた. (1)造血幹細胞は移植後、長管骨では骨端に近くの骨組織に接してhomingすることが明らかになり、造血幹細胞ニッチが存在することを示した。(2)造血幹細胞が血液ばかりでなく骨格筋、肝臓、網膜などに一部転換できることが明らかとなった。(3)ヒト造血幹細胞からのT細胞を含む全ての血球分化をin vivoで観察できるNOGマウスを開発した。ヒトT細胞の初期分化は主に胸腺内で行われ、一部胸腺外分化していると考えられた。ヒト造血幹細胞を移植したNOGマウスでのみ血清中にヒト型のIgM,IgG,IgAが観察された。(4)造血幹細胞増殖支持能を持つストローマ細胞株を樹立し、特異的に発現している遺伝子のクローニングを行った。候補遺伝子の絞り込みを行い、一つの遺伝子産物に対する抗体は造血幹細胞の一部を認識していた。このストローマ細胞株上でサルES細胞を培養すると非常に多くの血球が出現することから造血幹細胞を生み出すのに必要な分子も発現している可能性が示唆された。(5)G-CSFR遺伝子異常を持ちKostmann症候群のモデルとなる2種類のTgマウスを作成した。Wild type、G-CSFR-Tgマウス及び2種類の変異G-CSFR-TgマウスへG-CSFを1年間連日皮下すると、3血球系とも著明に増加した状態が続いたが、今のところ白血病の発生は見られていない。

研究成果
(31件)

すべてその他

すべて文献書誌 (31件)

[文献書誌] Mitsui T., Watanabe S, Nakahata T, et al.: "Impared neutrophil maturation in truncated G-CSF receptor transgenic mice."Blood. 101. 2990-2995 (2003)
[文献書誌] Akizawa, Y., Nishiyama, C., Nakahata T, et al.: "Regulation of human FcepsilonR1 beta chain gene expression by Oct-1."International Immunology. 15. 549-556 (2003)
[文献書誌] Umeda K., Adachi S, Nakahata T.et al.: "Successful T-cell-replete peripheral blood stem cell transplantation from HLA-haploidentical microchimeric mother to daughter with refractory acute lymphoblastic leukemia using reduced-intensity conditioning."Bone Marrow Transplant.. 31. 1061-1063 (2003)
[文献書誌] Hiramatsu H., Nishikomori R., Nakahata T, et al.: "Complete reconstitution of human lymphocytes from cord blood CD34+ cells using NOD/SCID/_<-c>~<null> mice model."Blood. 102. 873-880 (2003)
[文献書誌] Yoshimoto M., Shinohara T., Heike T, Nakahata, T et al.: "Direct visualization of transplanted hematopoietic cell reconstitution in intact mouse organs indicate the presence of a niche."Hematol.. 31. 733-740 (2003)
[文献書誌] Ishida D., Kometani K., Yang H., Nakahata T., et al.: "Myeloproliferative stem cell disorders by dysregulated Rapl activation in SPA-I-deficient mice."Cancer Cell. 4. 55-65 (2003)
[文献書誌] Umeda K., Yoshimoto M., Heike T., Nakahata T.: "Development of primitive and definitive hemayopoiesis from nonhuman primate embryonic stem cells in vitro."Development. (in press).
[文献書誌] Yagasaki H., Oda T., Nakahata T.et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC in the Japanese popuration. Hum."Mutat.. 21. 555(DOI: 10.1002/humu.9142) (2003)
[文献書誌] Yasumi T, Katamura K.Nakahata T. et al.: "Differential Requirement of the Cd40-CD154 costimulatory pathway during T helper cell priming by CD8_+and CD8_- murine dendritic cell subsets."J.Immunol.. (In press).
[文献書誌] Okada M., Imai T, Nakahata T.et al.: "A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells - caspase-independent, necrosis-like programmed cell death mediated by serine protease activity."Blood. (in press). (2003)
[文献書誌] Xu Y., Arai H., Zhuge X., Nakahata T, et al.: "Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice."Arterioscl.Throm.Vas.. (in press).
[文献書誌] Nishikomori R., Akutagawa H., Nakahata T.et al.: "X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role For NEMO in human T-cell development and/or survival."Blood. (in press).
[文献書誌] Lin YW, Watanabe K, Nakahata T, et al.: "Serial Granulocyte transfusions as a treatment for sepsis due to multidrug-resistant pseudomonas aeruginosa in a neutropenic patient."J Clin Microbiol. 41. 4892-4893 (2003)
[文献書誌] Imai T, Nishijo K, Nakahata T, et al.: "FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells."Oncogene. 22. 9231-9242 (2003)
[文献書誌] Heike T, Nakahata T.: "Stem cell plasticity in the hematopoietic system."Hematol.. 79. 7-14 (2003)
[文献書誌] Matsubara H, Watanabe K, Nakahata T. et al.: "Rapid improvement of paraplegia caused by epidural involvements of Burkitt's lymphoma with chemotherapy."Spine. 29. E4-E6 (2003)
[文献書誌] Adachi S., Leoni M., Carson DA, Nakahara T.: "Apoptosis induced by molecular targeting therapy in hematological malignancies."Acta Haematol.. 111. 107-123 (2004)
[文献書誌] Kambe N., Hiramatsu H, Nakahata T, et al.: "Development of both human connective tissue-type and mucosal-type mast cells in mice from hemacopoietic stem cells with identical distribution pattern to human body."Blood. 103. 860-867 (2004)
[文献書誌] Nishikomori R., Akutagawa H., Nakahata T.et al.: "X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival."Blood. (in press).
[文献書誌] Harazaki M., Kawai Y., Su L., Hamazaki Y., Nakahata T et al.: "Specific recruitment of SPA1 to the immunological synapse : involvement of actin-bundling protein actinin."Immunol. Letter. (in press).
[文献書誌] Hiroshi Yagasaki^1, Satoshi Hamanoue^<1, 2>, Nakahata T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Human Mutat.. (In press).
[文献書誌] Yagasaki H., Hamanoue S., Nakahata T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Human Mutat.. (In press).
[文献書誌] 中畑龍俊: "造血幹細胞を用いた再生医療"血夜・免疫・腫瘍. 8(1). 27-32 (2003)
[文献書誌] 中畑龍俊: "臍帯血利用ex vivo増幅"最新医学. 58. 57-62 (2003)
[文献書誌] 中畑龍俊: "幹細胞と再生医学"最新医学(2003年3月増刊号). 58. 527-536 (2003)
[文献書誌] 中畑龍俊: "再生医療の現状と課題"シスメックスジャーナル. 25. 1-9 (2003)
[文献書誌] 中畑龍俊: "再生医療の現状と課題"細胞工学. 22. 512-515 (2003)
[文献書誌] 中畑龍俊: "造血幹細胞を用いた再生医療"細胞工学. 22. 516-520 (2003)
[文献書誌] 平松英文, 平家俊男, 伊藤守, 中畑龍俊: "NOD/SCID/rs nullマウスを用いた新しいヒト造血幹細胞測定系の開発"臨床血液. 44. 193-197 (2003)
[文献書誌] 平松英文, 中畑龍俊: "NOD/SCID/rs nullマウス"血液・腫瘍科. 47. 46-51 (2003)
[文献書誌] Manabe A., Nakahata T: "Myelodysplastic and myeloproliferatine disorders in children (eds. Lopes L.F. & Hasle M) Tecmedd,"Experiences on MDS and JMML from Japan.. 317-324 (2003)

2003 年度 実績報告書

造血幹細胞の増殖・分化とその異常に関する研究

研究代表者

中畑 龍俊 京都大学, 医学研究科, 教授 (20110744)

研究成果

[文献書誌] Mitsui T., Watanabe S, Nakahata T, et al.: "Impared neutrophil maturation in truncated G-CSF receptor transgenic mice."Blood. 101. 2990-2995 (2003)

[文献書誌] Akizawa, Y., Nishiyama, C., Nakahata T, et al.: "Regulation of human FcepsilonR1 beta chain gene expression by Oct-1."International Immunology. 15. 549-556 (2003)

[文献書誌] Hiramatsu H., Nishikomori R., Nakahata T, et al.: "Complete reconstitution of human lymphocytes from cord blood CD34+ cells using NOD/SCID/_<-c>~<null> mice model."Blood. 102. 873-880 (2003)

[文献書誌] Yoshimoto M., Shinohara T., Heike T, Nakahata, T et al.: "Direct visualization of transplanted hematopoietic cell reconstitution in intact mouse organs indicate the presence of a niche."Hematol.. 31. 733-740 (2003)

[文献書誌] Ishida D., Kometani K., Yang H., Nakahata T., et al.: "Myeloproliferative stem cell disorders by dysregulated Rapl activation in SPA-I-deficient mice."Cancer Cell. 4. 55-65 (2003)

[文献書誌] Umeda K., Yoshimoto M., Heike T., Nakahata T.: "Development of primitive and definitive hemayopoiesis from nonhuman primate embryonic stem cells in vitro."Development. (in press).

[文献書誌] Yagasaki H., Oda T., Nakahata T.et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC in the Japanese popuration. Hum."Mutat.. 21. 555(DOI: 10.1002/humu.9142) (2003)

[文献書誌] Yasumi T, Katamura K.Nakahata T. et al.: "Differential Requirement of the Cd40-CD154 costimulatory pathway during T helper cell priming by CD8_+and CD8_- murine dendritic cell subsets."J.Immunol.. (In press).

[文献書誌] Okada M., Imai T, Nakahata T.et al.: "A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells - caspase-independent, necrosis-like programmed cell death mediated by serine protease activity."Blood. (in press). (2003)

[文献書誌] Xu Y., Arai H., Zhuge X., Nakahata T, et al.: "Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice."Arterioscl.Throm.Vas.. (in press).

[文献書誌] Nishikomori R., Akutagawa H., Nakahata T.et al.: "X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role For NEMO in human T-cell development and/or survival."Blood. (in press).

[文献書誌] Lin YW, Watanabe K, Nakahata T, et al.: "Serial Granulocyte transfusions as a treatment for sepsis due to multidrug-resistant pseudomonas aeruginosa in a neutropenic patient."J Clin Microbiol. 41. 4892-4893 (2003)

[文献書誌] Imai T, Nishijo K, Nakahata T, et al.: "FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells."Oncogene. 22. 9231-9242 (2003)

[文献書誌] Heike T, Nakahata T.: "Stem cell plasticity in the hematopoietic system."Hematol.. 79. 7-14 (2003)

[文献書誌] Matsubara H, Watanabe K, Nakahata T. et al.: "Rapid improvement of paraplegia caused by epidural involvements of Burkitt's lymphoma with chemotherapy."Spine. 29. E4-E6 (2003)

[文献書誌] Adachi S., Leoni M., Carson DA, Nakahara T.: "Apoptosis induced by molecular targeting therapy in hematological malignancies."Acta Haematol.. 111. 107-123 (2004)

[文献書誌] Kambe N., Hiramatsu H, Nakahata T, et al.: "Development of both human connective tissue-type and mucosal-type mast cells in mice from hemacopoietic stem cells with identical distribution pattern to human body."Blood. 103. 860-867 (2004)

[文献書誌] Nishikomori R., Akutagawa H., Nakahata T.et al.: "X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival."Blood. (in press).

[文献書誌] Harazaki M., Kawai Y., Su L., Hamazaki Y., Nakahata T et al.: "Specific recruitment of SPA1 to the immunological synapse : involvement of actin-bundling protein actinin."Immunol. Letter. (in press).

[文献書誌] Hiroshi Yagasaki^1, Satoshi Hamanoue^<1, 2>, Nakahata T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Human Mutat.. (In press).

[文献書誌] Yagasaki H., Hamanoue S., Nakahata T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Human Mutat.. (In press).

[文献書誌] 中畑龍俊: "造血幹細胞を用いた再生医療"血夜・免疫・腫瘍. 8(1). 27-32 (2003)

[文献書誌] 中畑龍俊: "臍帯血利用ex vivo増幅"最新医学. 58. 57-62 (2003)

[文献書誌] 中畑龍俊: "幹細胞と再生医学"最新医学(2003年3月増刊号). 58. 527-536 (2003)

[文献書誌] 中畑龍俊: "再生医療の現状と課題"シスメックスジャーナル. 25. 1-9 (2003)

[文献書誌] 中畑龍俊: "再生医療の現状と課題"細胞工学. 22. 512-515 (2003)

[文献書誌] 中畑龍俊: "造血幹細胞を用いた再生医療"細胞工学. 22. 516-520 (2003)

[文献書誌] 平松英文, 平家俊男, 伊藤守, 中畑龍俊: "NOD/SCID/rs nullマウスを用いた新しいヒト造血幹細胞測定系の開発"臨床血液. 44. 193-197 (2003)

[文献書誌] 平松英文, 中畑龍俊: "NOD/SCID/rs nullマウス"血液・腫瘍科. 47. 46-51 (2003)

[文献書誌] Manabe A., Nakahata T: "Myelodysplastic and myeloproliferatine disorders in children (eds. Lopes L.F. & Hasle M) Tecmedd,"Experiences on MDS and JMML from Japan.. 317-324 (2003)

2003 年度実績報告書

中畑龍俊京都大学, 医学研究科, 教授 (20110744)