2000 Fiscal Year Annual Research Report

造血幹細胞の増殖・分化とその異常に関する研究

Research Project

Project/Area Number	12215067
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
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)	林英蔚京都大学, 医学研究科, 助手 (40283600) 依藤亨京都大学, 医学研究科, 助手 (60220779)
Keywords	造血幹細胞 / 発生 / CD34 / AGM領域 / G-CSF受容体 / Kostmann症候群 / トランスジェニックマウス / 白血病
Research Abstract	成体マウスの造血幹細胞はCD34-細胞分画に存在するが、胎生期、新生児マウスの幹細胞はCD34抗原を強発現しており、造血幹細胞上のCD34抗原は陽性から陰性に年齢とともに変化していくことが初めて明らかとなった。再移植実験などの結果、この変化は環境によるのではなく、造血幹細胞自身に内蔵するtime clockがその発現を規定していると考えられた。造血幹細胞が初めて検出できる胎生10.5日のマウス胚のAGM領域から造血幹細胞の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造血幹細胞が発生する以前の卵黄嚢や胚体を共培養すると、長期骨髄再構築能を持った造血幹細胞が出現してくることが示された。すなわちこのストローマ細胞は造血幹細胞を生み出す(stem cell genesis)のに必要な分子も発現していると考えられた。今後この分子の同定を行う予定である。 wild typeおよびKostmann症候群患者で見られるG-CSF受容体(G-CSFR)遺伝子異常と同様の2種類の遺伝子異常(マウス717,730)を持つDNA fragmentを作成し、LDプロモーターに組み込み、型のごとくトランスジェニックマウス(Tgマウス)を作成した。Wild type G-CSFR Tgマウスでは末梢血に全く異常は見られなかった。一方、C末端を欠失した2種類の変異G-CSFR-Tgマウスでは共に好中球減少が見られ、Kostmann症候群のモデルとなることが明らかとなった。1種類の変異G-CSFR-TgマウスヘG-CSFを3ヶ月間、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ているが、今のところ白血病の発生は見られていない。

Research Products

(37 results)

All Other

All Publications (37 results)

[Publications] Futaki M.,Yamashita T.,Yabe M.,Kato S.,Nakahata T.: "The IVS4+4A-T mutation of the Fanconi Anemia gene FANCC is not associated with severe phenotype in Japanese patients."Blood. 95. 1493-1498 (2000)
[Publications] Sugiyama H.,Nonaka T.,Komoriya K.,Tsuji K.,Nakahata T.: "Peroxisome proliferator-activated receptors negatively regurate mast cell activation"FEBS Letters. 467. 259-262 (2000)
[Publications] Ueda Y,Tsuji K,Yoshino H,Ebihara Y,Yagasaki H,Yasukawa K,Nakahata T: "Expansion of human NOD/SCID-repopulating cells by a combination of stem cell factor, Flk2/Flt3 ligand, thrombopoietin and a complex of interleukin-6 and soluble interleukin-6 receptor"J Clin Invest. 105. 1013-1021 (2000)
[Publications] Hayashi Y.,Honma Y.,Niitsu N.,Tsuji K.,Nakahata T.: "SN-1, a novel leukemic cell line with t(11;16)(q23;p13) : Myeloid characteristics and resistance to retinoids and vitamin D3."Cancer Res.. 60. 1139-1145 (2000)
[Publications] Misawa K.,Nosaka T.,Morita S.,Nakahata T.,Asano S.,Kitamura T.: "A method to identify cDNA based on localization of green fluorescent protein fusion products."Proc.Natl.Acad.Sci.USA. 97. 3062-3066 (2000)
[Publications] Ebihara Y,Xu M,Nakahata T,Tsuji K: "Exclusive expression of G-CSF receptor on myeloid progenitors in bone marrow CD34+ cells"Br J Haematol. 109. 153-161 (2000)
[Publications] Ueda T,Manabe A,Kikuchi A,Yoshino H,Ebihara Y,Ishii-T,Tsuji K,Nakahata T: "Massive pericardial and pleural effusion with anasarca following allogeneic bone marrow transplantation"Int J Hematol. 71. 394-397 (2000)
[Publications] Ueda T,Yoshino H,Kobayashi K,Asano S,Nakahata T,Tsuji K: "Hematopoietic repopulating ability of cord blood CD34+ cells in NOD/Shi-scid mice"Stem Cells. 18. 204-213 (2000)
[Publications] Matsui A.,Sato T.,Maekawa T.,Asano S.,Nakahata T.,Tsuji K.: "Glycoprotein 130 and c-kit signals synergistically induce thrombopoietin production by hematopoietic cells"Int.J.Hematol. 72. 455-462 (2000)
[Publications] Sato T,Maekawa T,Watanabe S,Tsuji K,Nakahata T: "Erythroid progenitors differentiate and mature in response to endogenous erythropoietin"J Clin Invest. 106. 263-270 (2000)
[Publications] Sasaki S,Ito E,Toki T,Maekawa T,Nakahata T,Igarashi K,Yokoyama M: "Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15"Oncogene.. 19. 3739-3749 (2000)
[Publications] Tanaka Y,Naruse I,Xu M,Nakahata T,Maekawa T,Ishii S : "Extensive brain hemorrhage and embyonic lethality in a mouse null mutant of CREB-binding protein."Mechanisms of Development. 95. 133-145 (2000)
[Publications] Ishii T,Manabe A,Ebihara Y,Nakahata T,Asano S,Tuji K: "Improvement in bronchiolitis obliterans organizing pneumonia in a chlid after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin"Bone Marrow Transplantation.. 26. 907-910 (2000)
[Publications] Muroi J,Yorifuji T,Uematsu A,Kitamura A,Nakahata T: "Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylgutaryl CoA lyase (HL) deficiency"Hum Genet.. 107. 320-326 (2000)
[Publications] Muroi J,Yorifuji T,Uematsu A,Nakahata T: "Cerebral infarction and pancreatitis : possible complications of patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency"J.Inherit.Metab.Dis.. 23. 636-637 (2000)
[Publications] Higuchi Y,Hattori H,Tsuji M,Asato R,Nakahata T: "Partial seizures in leukoencephalopathy with swelling and a discrepantly mild clinical course"Brain & Development. 22. 387-389 (2000)
[Publications] Nakahata T.: "Ex vivo expansion of human hematopoietic stem cells"Int J Hematol.. 73(1). 6-13 (2001)
[Publications] Yoshino H,Ueda T,Kawahata M,Asano S,Nakahata T,Tsuji K: "Natural killer cell depletion by ant asialo GM1 antiserum treatment enhances human hematopoietic stem cell engraftment in NOD/Shi-scid mice"Bone Marrow Transplant. (in press).
[Publications] Sugiyama H,Nonaka T,Tsuji K,Nakahata T: "Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells"FEBS Lett,. (in press).
[Publications] Ma F,Yang F,Kaneko A,Asano S,Nakahata T,Tsuji K: "Cytokine requirement for the development of T-lineage potential from lymphohematopoietic progenitor cells"Br J Haematol,. (in press).
[Publications] Matsuoka S,Ebihara Y,Xu M,Ikeda Y,Nakahata T,Tsuji K: "CD34 expression on long-term repopulating hematopoietic stem cells changes during developmental stages"Blood. (in press).
[Publications] Xu M,Matsuoka S,Yang F-C,Asano S,Nakahata T,Tsuji K: "Evidence for the presence of primitive megakaryopoiesis in the early yolk sac"Blood. (in press).
[Publications] Yamashita T,Nakahata T.: "Current knowledge on the pathophysiology of fanconi anemia : from genes to pheotypes"Int J Hematol. (in press).
[Publications] Nishikawa M.,Tahara T.,Nakahata T.,Shimosaka A.: "Role of the microenvironment of the embryonic aorta-gonad-mesonephros region in hematopoiesis"Stem Cells. (in press).
[Publications] Sawano A.,Iwai S.,Sakurai Y.,Nakahata T.,Shibuya M.: "Vascular endothelial growth factor receptor-1(Flt-1) is a novel cell surface marker for the lineage of monocyte-macrophages in humans"Blood. (in press).
[Publications] Matsuoka S,Tsuji K,Ikeda Y,Asano S.,Nakahata T: "Generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleura by AGM region-derived stromal cells"Blood. (in press).
[Publications] Ma F.,Wada M.,Yoshino,H.,Nakahata,T.,Asano,S.,Tsuji,K.: "Development of human lymphohematopoietic stem/progenitor cells defined by CD34 and CD81 expressions"Blood. (in press).
[Publications] 中畑龍俊: "造血幹細胞のex vivo増幅と臨床応用"Biotherapy. 14. 270-275 (2000)
[Publications] 中畑龍俊: "ヒトES細胞と再生医療"BIO Clinica. 15(6). 322-326 (2000)
[Publications] 久保田優,濱畑啓悟,渡邉健一郎,林英蔚,小石誠二,宇佐美郁哉,中畑龍俊,秋山祐一: "小児赤白血病の3症例:予後因子の文献的考察"臨床血液. 41(3). 212-217 (2000)
[Publications] 中畑龍俊: "造血幹細胞と造血前駆細胞"血液・免疫・腫瘍. 5(3). 251-256 (2000)
[Publications] 前川平,石井武文,西原政道,中畑龍俊: "ヒト造血細胞におけるケモカイン受容体CXCR4の発現動態とその臨床的意義."臨床免疫. 33(1). 99-105 (2000)
[Publications] 中畑龍俊: "造血幹細胞のex vivo増幅と臨床応用"遺伝子医学. 4(2). 246-250 (2000)
[Publications] 今井剛,瀧本哲也,秋山祐一,足立壮一,久保田優,中畑龍俊: "寛解導入不能の縦隔原発T細胞性非ホジキンリンパ腫3例の臨床的検討"日小血会誌. 14. 141-146 (2000)
[Publications] Nakahata T,Xu M,Ueda T,Matsuoka S,Ito M,Tsuji K: "Cell Therapy"Springer. 3 (2000)
[Publications] 中畑龍俊: "サイトカインの造血幹細胞移植への応用"羊土社. 6 (2000)
[Publications] 中畑龍俊: "サイトカインと疾患 1"医学のあゆみ. 5 (2000)

2000 Fiscal Year Annual Research Report

造血幹細胞の増殖・分化とその異常に関する研究

Principal Investigator

中畑 龍俊 京都大学, 医学研究科, 教授 (20110744)

Research Products

[Publications] Futaki M.,Yamashita T.,Yabe M.,Kato S.,Nakahata T.: "The IVS4+4A-T mutation of the Fanconi Anemia gene FANCC is not associated with severe phenotype in Japanese patients."Blood. 95. 1493-1498 (2000)

[Publications] Sugiyama H.,Nonaka T.,Komoriya K.,Tsuji K.,Nakahata T.: "Peroxisome proliferator-activated receptors negatively regurate mast cell activation"FEBS Letters. 467. 259-262 (2000)

[Publications] Hayashi Y.,Honma Y.,Niitsu N.,Tsuji K.,Nakahata T.: "SN-1, a novel leukemic cell line with t(11;16)(q23;p13) : Myeloid characteristics and resistance to retinoids and vitamin D3."Cancer Res.. 60. 1139-1145 (2000)

[Publications] Misawa K.,Nosaka T.,Morita S.,Nakahata T.,Asano S.,Kitamura T.: "A method to identify cDNA based on localization of green fluorescent protein fusion products."Proc.Natl.Acad.Sci.USA. 97. 3062-3066 (2000)

[Publications] Ebihara Y,Xu M,Nakahata T,Tsuji K: "Exclusive expression of G-CSF receptor on myeloid progenitors in bone marrow CD34+ cells"Br J Haematol. 109. 153-161 (2000)

[Publications] Ueda T,Manabe A,Kikuchi A,Yoshino H,Ebihara Y,Ishii-T,Tsuji K,Nakahata T: "Massive pericardial and pleural effusion with anasarca following allogeneic bone marrow transplantation"Int J Hematol. 71. 394-397 (2000)

[Publications] Ueda T,Yoshino H,Kobayashi K,Asano S,Nakahata T,Tsuji K: "Hematopoietic repopulating ability of cord blood CD34+ cells in NOD/Shi-scid mice"Stem Cells. 18. 204-213 (2000)

[Publications] Matsui A.,Sato T.,Maekawa T.,Asano S.,Nakahata T.,Tsuji K.: "Glycoprotein 130 and c-kit signals synergistically induce thrombopoietin production by hematopoietic cells"Int.J.Hematol. 72. 455-462 (2000)

[Publications] Sato T,Maekawa T,Watanabe S,Tsuji K,Nakahata T: "Erythroid progenitors differentiate and mature in response to endogenous erythropoietin"J Clin Invest. 106. 263-270 (2000)

[Publications] Sasaki S,Ito E,Toki T,Maekawa T,Nakahata T,Igarashi K,Yokoyama M: "Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15"Oncogene.. 19. 3739-3749 (2000)

[Publications] Tanaka Y,Naruse I,Xu M,Nakahata T,Maekawa T,Ishii S : "Extensive brain hemorrhage and embyonic lethality in a mouse null mutant of CREB-binding protein."Mechanisms of Development. 95. 133-145 (2000)

[Publications] Ishii T,Manabe A,Ebihara Y,Nakahata T,Asano S,Tuji K: "Improvement in bronchiolitis obliterans organizing pneumonia in a chlid after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin"Bone Marrow Transplantation.. 26. 907-910 (2000)

[Publications] Muroi J,Yorifuji T,Uematsu A,Kitamura A,Nakahata T: "Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylgutaryl CoA lyase (HL) deficiency"Hum Genet.. 107. 320-326 (2000)

[Publications] Muroi J,Yorifuji T,Uematsu A,Nakahata T: "Cerebral infarction and pancreatitis : possible complications of patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency"J.Inherit.Metab.Dis.. 23. 636-637 (2000)

[Publications] Higuchi Y,Hattori H,Tsuji M,Asato R,Nakahata T: "Partial seizures in leukoencephalopathy with swelling and a discrepantly mild clinical course"Brain & Development. 22. 387-389 (2000)

[Publications] Nakahata T.: "Ex vivo expansion of human hematopoietic stem cells"Int J Hematol.. 73(1). 6-13 (2001)

[Publications] Yoshino H,Ueda T,Kawahata M,Asano S,Nakahata T,Tsuji K: "Natural killer cell depletion by ant asialo GM1 antiserum treatment enhances human hematopoietic stem cell engraftment in NOD/Shi-scid mice"Bone Marrow Transplant. (in press).

[Publications] Sugiyama H,Nonaka T,Tsuji K,Nakahata T: "Peroxisome proliferator-activated receptors are expressed in mouse bone marrow-derived mast cells"FEBS Lett,. (in press).

[Publications] Ma F,Yang F,Kaneko A,Asano S,Nakahata T,Tsuji K: "Cytokine requirement for the development of T-lineage potential from lymphohematopoietic progenitor cells"Br J Haematol,. (in press).

[Publications] Matsuoka S,Ebihara Y,Xu M,Ikeda Y,Nakahata T,Tsuji K: "CD34 expression on long-term repopulating hematopoietic stem cells changes during developmental stages"Blood. (in press).

[Publications] Xu M,Matsuoka S,Yang F-C,Asano S,Nakahata T,Tsuji K: "Evidence for the presence of primitive megakaryopoiesis in the early yolk sac"Blood. (in press).

[Publications] Yamashita T,Nakahata T.: "Current knowledge on the pathophysiology of fanconi anemia : from genes to pheotypes"Int J Hematol. (in press).

[Publications] Nishikawa M.,Tahara T.,Nakahata T.,Shimosaka A.: "Role of the microenvironment of the embryonic aorta-gonad-mesonephros region in hematopoiesis"Stem Cells. (in press).

[Publications] Sawano A.,Iwai S.,Sakurai Y.,Nakahata T.,Shibuya M.: "Vascular endothelial growth factor receptor-1(Flt-1) is a novel cell surface marker for the lineage of monocyte-macrophages in humans"Blood. (in press).

[Publications] Matsuoka S,Tsuji K,Ikeda Y,Asano S.,Nakahata T: "Generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleura by AGM region-derived stromal cells"Blood. (in press).

[Publications] Ma F.,Wada M.,Yoshino,H.,Nakahata,T.,Asano,S.,Tsuji,K.: "Development of human lymphohematopoietic stem/progenitor cells defined by CD34 and CD81 expressions"Blood. (in press).

[Publications] 中畑龍俊: "造血幹細胞のex vivo増幅と臨床応用"Biotherapy. 14. 270-275 (2000)

[Publications] 中畑龍俊: "ヒトES細胞と再生医療"BIO Clinica. 15(6). 322-326 (2000)

[Publications] 久保田優,濱畑啓悟,渡邉健一郎,林英蔚,小石誠二,宇佐美郁哉,中畑龍俊,秋山祐一: "小児赤白血病の3症例:予後因子の文献的考察"臨床血液. 41(3). 212-217 (2000)

[Publications] 中畑龍俊: "造血幹細胞と造血前駆細胞"血液・免疫・腫瘍. 5(3). 251-256 (2000)

[Publications] 前川平,石井武文,西原政道,中畑龍俊: "ヒト造血細胞におけるケモカイン受容体CXCR4の発現動態とその臨床的意義."臨床免疫. 33(1). 99-105 (2000)

[Publications] 中畑龍俊: "造血幹細胞のex vivo増幅と臨床応用"遺伝子医学. 4(2). 246-250 (2000)

[Publications] 今井剛,瀧本哲也,秋山祐一,足立壮一,久保田優,中畑龍俊: "寛解導入不能の縦隔原発T細胞性非ホジキンリンパ腫3例の臨床的検討"日小血会誌. 14. 141-146 (2000)

[Publications] Nakahata T,Xu M,Ueda T,Matsuoka S,Ito M,Tsuji K: "Cell Therapy"Springer. 3 (2000)

[Publications] 中畑龍俊: "サイトカインの造血幹細胞移植への応用"羊土社. 6 (2000)

[Publications] 中畑龍俊: "サイトカインと疾患 1"医学のあゆみ. 5 (2000)

中畑龍俊京都大学, 医学研究科, 教授 (20110744)