2003 Fiscal Year Annual Research Report

ES細胞、組織幹細胞の増殖・分化機構の解明とその臨床応用に関する研究

Research Project

Project/Area Number	13GS0009
Research Institution	Kyoto University
Principal Investigator	中畑龍俊京都大学, 医学研究科, 教授 (20110744)
Co-Investigator(Kenkyū-buntansha)	依藤亨京都大学, 医学研究科, 講師 (60220779) 西小森隆太京都大学, 医学研究科, 助手 (70359800) 平家俊男京都大学, 医学研究科, 助教授 (90190173) 足立壮一京都大学, 医学研究科, 助手 (10273450)
Keywords	ES細胞 / 造血幹細胞 / 体性幹細胞 / 自己複製因子 / 可塑性 / 移植 / ex vivo増幅 / 遺伝子クローニング
Research Abstract	体性幹細胞の種類とその細胞生物学性状、自己複製、増殖、分化、形質転換に関与する分子を明らかにすること、また、マウス、サルES細胞から体性幹細胞への分化誘導に特異的に作用する分子を明らかにし、その遺伝子をクローニングすることを目的として実験を行い以下の成果が得られた。 (1).NOD/SCID/γ_c^<-/->(NOG)マウスを開発した。このマウスを用いることによりT細胞を含むすべてのヒト型血球を造血幹細胞からin vivoで誘導することが可能となった。ヒト造血幹細胞からのT細胞分化はほとんどがマウス胸腺内で起こり、一部胸腺外分化することが明らかとなった。また、生成されるT, B倍亡は機能を有しており、マウス血清中にヒト型IgG,IgM,IgAが検出された。(2).NOGマウスを用いてヒト造血幹細胞の可塑性を検討した。臍帯血CD34+細胞はマウス中で肝細胞に分化できることが示された。現在ヒト造血幹細胞の可塑性を検討中である。(3).GFP-Tgマウス造血幹細胞が血液ばかりでなく骨格筋、肝臓、網膜などに転換できることが明らかとなった。(4)神経幹細胞に特異的に発現し、分化とともに減弱していく新たな遺伝子を5個クローニングした。現在、その機能解析を進めるとともにノックアウトマウスを作成中である。(5).マウスES細胞から神経幹細胞を特異的に誘導する系を確立した。ES細胞から特異的に誘導した神経幹細胞は自己複製能と神経細胞、グリア細胞への分化能を保持していた。(6).マウスES細胞から分化させた、FLK1+細胞は血液、血管内皮、心筋に分化できる.ことから3者に共通の母細胞の存在が示唆された。(7)サルES細胞から胎児型の血液細胞と成体型の血液細胞の両者および血管内皮細胞を誘導することが可能となった。サルでも血液と血管内皮の共通の母細胞であるhemangioblastの存在が明らかとなった。

Research Products

(35 results)

All Other

All Publications (35 results)

[Publications] Mitsui T., Watanabe S., Nakahata T.et al.: "Impared neutrophil maturation in truncated G-CSF receptor transgenic mice."Blood. 101. 2990-2995 (2003)
[Publications] Akizawa, Y., Nishiyama, C., Nakahata, T.et al.: "Regulation of human Fcepsilon RI beta chain gene expression by Oct-1."International Immunology. 15. 549-556 (2003)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Ishida D, Kometani K., Yang H., Nakahata, T.et al.: "Myeloproliferative stem cell disorders by dysregulated Rap1 activation in SPA-1-deficient mice."Cancer Cell. 4. 55-65 (2003)
[Publications] 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)
[Publications] 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)
[Publications] Heike T., Nakahata T.: "Stem cell plasticity in the hematopoietic system."Hematol.. 79. 7-14 (2003)
[Publications] 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)
[Publications] Adachi S., Leoni M., Carson DA, Nakahata T.: "Apoptosis induced by molecular targeting therapy in hematological malignancies."Acta Haematol.. 111. 107-123 (2004)
[Publications] Kambe N., Hiramatsu H, Nakahata, T.et al.: "Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body."Blood. 103. 860-867 (2004)
[Publications] 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).
[Publications] 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)
[Publications] 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).
[Publications] 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)
[Publications] 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).
[Publications] 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).
[Publications] 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).
[Publications] 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).
[Publications] 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).
[Publications] 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).
[Publications] 中畑龍俊: "造血幹細胞を用いた再生医療"血液・免疫・腫瘍. 8(1). 27-32 (2003)
[Publications] 中畑龍俊: "臍帯血利用 ex vivo増幅"最新医学. 58. 57-62 (2003)
[Publications] 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)
[Publications] 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)
[Publications] 中畑龍俊: "再生医療の現状と課題"細胞工学. 22. 512-515 (2003)
[Publications] 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)
[Publications] 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)
[Publications] 平松英文, 中畑龍俊: "NOD/SCID/rs nullマウス"血液・腫瘍科. 47. 46-51 (2003)
[Publications] 中畑龍俊: "造血幹細胞の体外増幅と臨床応用への可能性"内科. 92. 537-542 (2003)
[Publications] 中畑龍俊: "再生医療のこれから"シスメックスジャーナル. 26. 59-68 (2003)
[Publications] 中畑龍俊: "造血幹細胞移植の最近の進歩"炎症と免疫. 12. 1-2 (2004)
[Publications] 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)
[Publications] 中畑龍俊: "再生医学分子生物学イラストレイテッド(改訂第2版)"(株)羊土社. 358-360 (2003)

2003 Fiscal Year Annual Research Report

ES細胞、組織幹細胞の増殖・分化機構の解明とその臨床応用に関する研究

Principal Investigator

中畑 龍俊 京都大学, 医学研究科, 教授 (20110744)

Research Products

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

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

[Publications] 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)

[Publications] 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)

[Publications] Ishida D, Kometani K., Yang H., Nakahata, T.et al.: "Myeloproliferative stem cell disorders by dysregulated Rap1 activation in SPA-1-deficient mice."Cancer Cell. 4. 55-65 (2003)

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

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

[Publications] 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).

[Publications] 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)

[Publications] 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).

[Publications] 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)

[Publications] 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).

[Publications] 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).

[Publications] 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).

[Publications] 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).

[Publications] 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).

[Publications] 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).

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

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 中畑龍俊: "造血幹細胞の体外増幅と臨床応用への可能性"内科. 92. 537-542 (2003)

[Publications] 中畑龍俊: "再生医療のこれから"シスメックスジャーナル. 26. 59-68 (2003)

[Publications] 中畑龍俊: "造血幹細胞移植の最近の進歩"炎症と免疫. 12. 1-2 (2004)

[Publications] 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)

[Publications] 中畑龍俊: "再生医学分子生物学イラストレイテッド(改訂第2版)"(株)羊土社. 358-360 (2003)

中畑龍俊京都大学, 医学研究科, 教授 (20110744)