造血幹細胞の増殖・分化とその異常に関する研究

2004 Fiscal Year Annual Research Report

• Project/Area Number: 12215067
• 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) ; 足立 壮一 京都大学, 医学研究科, 講師 (10273450)
• Keywords: 白血球 / サイトカイン / 造血幹細胞 / G-CSFR / hemangioblast / Kostmann症候群 / ES細胞 / トランスジェニックマウス

Research Abstract

造血幹細胞の発生、性状、増殖・分化機構とその異常、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研究を行い以下の成果が得られた。
(1)ヒト造血幹細胞を容易に受け入れるNOD/SCID/γ_c^<-/->(NOG)マウスを開発した。このマウスに移植したヒト臍帯血CD34+細胞からサイトカインの投与なしに顆粒球、赤芽球、マクロファージ、巨核球、血小板、T, B, NK, NKT, DC,肥満細胞を含む全てのヒト型血球分化が認められた。ヒトT細胞の初期分化は主に胸腺内で行われ、一部胸腺外分化も認められ、血清中にヒト型のIgM, IgG, IgAが観察された。
(2)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。
(3)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。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、白血病の発生は見られなかった。
(4)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。サルでもマウスと同様、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

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• [Journal Article] 造血系幹細胞 (2005)
  • Author(s): 中畑龍俊
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• [Journal Article] Development of primitive and definitive hematopoiesis from nonhuman primate embryonic stem cells in vitro. (2004)
  • Author(s): Umeda K., Heike T., Yoshimoto M., Shiota M., Suemori H., Luo H.Y., Chui D.H.K., Shibuya M., Nakatsuji N., Nakahata T.
  • Journal Title: Development 131 Pages: 1869-1879
• [Journal Article] 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. (2004)
  • Author(s): Kambe N.hiramatsu H., SnimonaKa M., Fujino H., Nishikomori R., Heike T.Ito M., kobayashi K., Ueyama Y., Matsuyoshi N., Miyachi Y., Nakahata T.
  • Journal Title: Blood 103 Pages: 860-867
• [Journal Article] Rapid improvement of paraplegia caused by epidural involvements of Burkitt's lymphoma with chemotherapy (2004)
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• [Journal Article] Differential Requirement of the Cd40-CD154 costimulatory pathway during Th cell priming by CD8a+ and CD8a- murine dendritic cell subsets. (2004)
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• [Journal Article] 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. (2004)
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• [Journal Article] Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys : phenotypicallydiscordant recurrence of a mutation in the hepatocyte nuclear factor 1b gene due to germ-line mosaicism. J. Clin. Endo. (2004)
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• [Journal Article] Living-related liver transplantation for propioric academia. J.Inherit (2004)
  • Author(s): Yorifuji T., Kawai M., Mamada M., Kurokawa K, Egawa H., Shigematsu Y., Kohno Y., Tanaka K., Nakahata T.
  • Journal Title: Metab.Dis. 27 Pages: 205-210
• [Journal Article] 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. (2004)
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  • Journal Title: Blood 103 Pages: 4565-4572
• [Journal Article] Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population. (2004)
  • Author(s): Yagasaki H., Hamanoue S, Oda T., Nakahata T., Asano S., Yamashita T.
  • Journal Title: Human Mutat 24 Pages: 481-490
• [Journal Article] Successful allogeneic bone marrow transplantation in apatient with acute myelogenous leukemia and cytomegalovirus retinitis. (2004)
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• [Journal Article] Second transplantation from HLA2-loci-mismatched mother for graft failure due to hemophagocytic syndrome after cord blood transplantation. (2004)
  • Author(s): Tanaka T., Matsubara H., Adachi S., Chang H., Fujino H, Yasumi T.Kobayashi M., Watanabe K, Takahashi M., kobayashi Y., Maruya E., Saji H., Nakahata T.
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• [Journal Article] Viral infections in juvenile myelo-monocytic leukemia : Prevalence and clinical implications. (2004)
  • Author(s): Manabe A., Tsurusawa M., Manabe A., Hayashi Y., Akiyama Y., Kigasawa H., Inada H., Noguchi Y., Sawai N., Kobayashi R., Nagatoshi, Y., Kawakami K., Nakahata T.
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• [Journal Article] Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice. (2004)
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• [Journal Article] Identification of cardiac stem cells with FLK1 expression during embryonic stem cell differentiation. (2004)
  • Author(s): Iida M., Heike T., Yoshimoto M., Baba S., Doi H., Nakahata T.
  • Journal Title: FASEB J. 19 Pages: 371-378
• [Journal Article] Generation of multipotent stem cells from postnatal mouse testis. (2004)
  • Author(s): Kanatsu-Shinohara M., Inoue K., Lee J., Yoshimoto M., Ogonuki N., Miki H., Baba T., Kazuki Y., Toyokuni S., Oshimura M., Heike T., Nakahata T., Ishino F., Ogura A., Shinohara T
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• [Journal Article] Specific recruitment of SPA1 to the immunological synapse : involvement of actin bundling protein actinin. (2004)
  • Author(s): Harazaki M., Kawai Y., Su L., Hamazaki Y., Nakahata T., Minato N., Hattori M.
  • Journal Title: Immunol.Letter 92 Pages: 221-226
• [Journal Article] 造血幹細胞移植の最近の進歩 (2004)
  • Author(s): 中畑龍俊
  • Journal Title: 炎症と免疫 12(1) Pages: 1-2
• [Journal Article] 新しいヒト造血幹細胞の測定系 (2004)
  • Author(s): 平松英文, 中畑龍俊
  • Journal Title: 炎症と免疫 12(1) Pages: 11-17
• [Journal Article] 硬化性胆管炎から肝硬変に進行し生体肝移植を受けたランゲルハンス細胞組織球症の1例 (2004)
  • Author(s): 松原央, 渡邊健一郎, 小林道広, 足立壮一, 柴田実, 清益功浩, 橋本尚子, 秋山祐一, 中畑龍
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• [Journal Article] 再生医療の現状と問題点 (2004)
  • Author(s): 中畑龍俊
  • Journal Title: Inflammation and Regeneration 24(2) Pages: 84-91
• [Journal Article] 造血幹細胞移植と再生医療 (2004)
  • Author(s): 中畑龍俊
  • Journal Title: 再生医療 3(1) Pages: 33-41
• [Journal Article] 再生医療の新たな展開 (2004)
  • Author(s): 中畑龍俊
  • Journal Title: 分子リウマチ 1(3) Pages: 67-72
• [Journal Article] 臍帯血移植 (2004)
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  • Journal Title: 治療学 38(10) Pages: 39-43
• [Journal Article] Cranial aneurysmal bone cystで発症したランゲルハンス細胞組織球症の女児例 (2004)
  • Author(s): 宮崎真紀, 平松英文, 國貞佳世, 徳舛麻友, 水嶋康浩, 松原央, 小林道弘, 足立壮一, 中畑龍
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• [Journal Article] 造血幹細胞移植医療とトランスレーショナルリサーチ (2004)
  • Author(s): 中畑龍俊
  • Journal Title: 血液フロンティア 14(11) Pages: 51-61
• [Journal Article] Characterization of mouse hepatic stem/progenytor cells, in a novel culture system.
  • Author(s): Tsuchiya A., Heike T., Fujino H., Shiota M., Umeda K., Yoshimoto M., Matsuda Y., Ichida T., Aoyagi Y., Nakahata T.
  • Journal Title: Gastroenterology (in press)
• [Journal Article] Two different role of purified Cd45+ hematopoietic stem cells after transplantation in muscles.
  • Author(s): Yoshimoto M., Heike T., Shiota M., Kobatashi H., Umeda K., Nakahata T.
  • Journal Title: Stem Cells (in press)
• [Journal Article] Prospective characterization of neural stem cells by flow cytometry analysis using combination of the surface markers.
  • Author(s): Nagato M., Heike T., Kato T., Yamanaka Y., Yoshimoto M., Shimazaki T., Okano H., Nakahata T.
  • Journal Title: J.Neurosci.Res. (in press)
• [Journal Article] Suplatast tosilate inhibits human mast cell development from cord blood progenitors.
  • Author(s): Kambe N., Nakahata T.Miyachi Y.
  • Journal Title: Allergology International. (In press)
• [Journal Article] Therapy-related myelodysplastic syndrome in childhood : A retrospective study of 36 patients in Japan.
  • Author(s): Tsurusawa M., Manabe A., Hayashi Y., Akiyama Y., Kigasawa H., Inada H., Noguchi Y., Sawai N., Kobayashi k., Nagatoshi Y., Kawakami K., Nakahata T
  • Journal Title: Leukemia Res. (in press)
• [Journal Article] Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia.
  • Author(s): Hasegawa D., Manabe A., Kubota T., Kawasaki H., Hirose I., Ohtsuka Y., Tsuruta T., Ebihara Y., Goto Y., Yan Zhao X., Sakashita K., Koike K., Isomura M., Kojima S., Hoshika A., Tsuji k., Nakahata T
  • Journal Title: Brit.J.Haematol (In press)
• [Journal Article] Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes.
  • Author(s): Kawamura T., Ono K., Morimoto T., Wada H., Hirai M., Hidaka K., Morisaki T., Heike T., Nakahata T., Kita T., Hasegawa K.
  • Journal Title: J.Biol.Chem. (In press)
• [Book] Chapter13「IL-6」サイトカイン・ケモカインのすべて-基礎から最新情報まで-(第三版 改訂新版) (2004)
  • Author(s): 吉崎和幸, 石橋敏幸, 中畑龍俊
  • Total Pages: 142-164
  • Publisher: 日本医学館
• [Book] Chapter57「造血構造とサイトカイン」 サイトカイン・ケモカインのすべて-基礎から最新情報まで-(第三版 改訂新版) (2004)
  • Author(s): 中畑龍俊
  • Total Pages: 621-632
  • Publisher: 日本医学館