新たなヒト化マウスの開発と再生医学への応用

• 研究課題/領域番号: 12357002
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 展開研究
• 研究分野: 人体病理学
• 研究機関: 国立成育医療センター(研究所) (2001-2002); 慶應義塾大学 (2000)
• 研究代表者: 秦 順一 国立成育医療センター(研究所), 所長 (90051614)
• 研究分担者: 藤本 純一郎 国立成育医療センター(研究所), 発生分化研究部, 部長 ; 山田 健人 慶應義塾大学, 医学部, 講師 (60230463) ; 清河 信敬 国立成育医療センター(研究所), 発生分化研究部, 室長 ; 梅澤 明弘 国立成育医療センター(研究所), 生殖医療研究部, 部長 (70213486) ; 桜田 一洋 協和発酵工業株式会社, 東京研究所, 研究員 ; 清河 信隆 国立成育医療センター研究所, 形態発生研究室, 室長 ; 渡辺 守 東京医科歯科大学, 医学部, 教授 (10175127) ; 穂積 信道 東京理科大学, 生命科学研究所, 教授 (60051744)
• 研究期間 (年度): 2000 – 2002
• 研究課題ステータス: 完了 (2002年度)
• 配分額: 43,200千円 (直接経費: 36,000千円、間接経費: 7,200千円); 2002年度: 15,600千円 (直接経費: 12,000千円、間接経費: 3,600千円); 2001年度: 15,600千円 (直接経費: 12,000千円、間接経費: 3,600千円); 2000年度: 12,000千円 (直接経費: 12,000千円)
• キーワード: 再生 / 骨粗鬆症 / 腫瘍血管 / 肝炎 / 心筋 / 骨髄間質 / 細胞移植 / 骨粗しょう症

研究概要

疾病に対する新たな治療法として、ヒトから採取された細胞・組織の応用が注目されている。特に患者から得られる細胞を増殖.分化させ、患者本人に戻す治療法は、拒絶がないことから最も理にかなった治療法である。そのためには各種の細胞を体外で増殖させ、さらに特定の方向に分化誘導する技術が極めて重要である。本研究では、新たな医用材料の開発研究として、ヒト骨髄間葉系幹細胞に着目し、主に心筋細胞、神経鞘細胞、内皮細胞への分化誘導法ならびに前臨床試験として免疫不全マウスへのこれらヒト組織の移植をおこなった。まず、ヒト骨髄間葉系幹細胞の心筋細胞への分化誘導法の確立を行い、細胞が採取しやすいヒト骨髄から、心筋細胞を得た。心筋症、心筋梗塞などの心疾患は、現在のところ心臓移植でしか救命できないことから必要性が高い。本研究で、NOD/SCIDマウス心臓へのヒト心筋細胞の移植実験が可能であることを明らかにしたことから、本実験系が前臨床的な生体内での詳細なデータを入手し、安全性の評価ならびに治療効果の推測を行う上で有用であることが判明した。またNOD/SCIDマウスへ、ヒト骨・肝を移植することでヒト化マウス(SCID-hu)を作成し、ヒト骨形成、造血、血管新生、肝再生モデルを開発し得たことから、ヒトでの造血、骨、血管、肝への薬剤の影響に対するスクリーニングや、これらの正常組織の再生を促進する物質の探索にも有用と思われる。さらに腫瘍血管新生モデル、C型肝炎ウイルス感染モデルの確立の成功は、これらの疾患の分子機構を生体レベルで明らかにするだけでなく、新たな薬剤の効果の判定、遺伝子治療の安全性・効率評価などに需要であり、前臨床試験の材料として汎用されることが期待される。このように本研究は、新しい材料(実験動物、医用材料)の開発に関する研究であり、その実用化へ向けた重要な基礎的検討を推進しえたものと確信する。また近年の動物実験の制限化を考慮すると、現在、病院医療廃棄物となっているヒト手術材料をインフォームドコンセントのもとに有効に利用していく本研究は、動物実験の縮小化の推進のみならず、ヒトでの細胞・組織の知見が得られることから、今後の医学研究にきわめて有効な方向性を示せたものと考える。

研究成果

• [雑誌論文] The use of isolated mature osteoblasts in abundance acts as desired-shaped bone regeneration in combination with a modified poly DL-lactic- co-glycolic acid(PLGA)-collagen sponge. (2003)
  • 著者名/発表者名: Ochi,K., Chen,G, Ushida,T., Gojo,S., Segawa,K., Tai,H., Ueno,K., Ohkawa,H., Mori,T., Toyama,Y., Hata,J, Umezawa,A.
  • 雑誌名: J.Cell. Physiol 194 ページ: 45-53
  • 説明: 「研究成果報告書概要(和文)」より
  • 査読あり
• [雑誌論文] The use of isolated mature osteoblasts in abundance acts as desired-shaped bone regeneration in combination with a modified poly DL-lactic- co-glycolic acid(PLGA)-collagen sponge (2003)
  • 著者名/発表者名: Ochi, K., Chen, G., Ushida, T., Gojo, S., Segawa, K., Tai, H., Ueno, K., Ohkawa, H., Mori, T., Toyama, Y., Hata, J, Umezawa, A.
  • 雑誌名: J.Cell.Physiol. 194 ページ: 45-53
  • 説明: 「研究成果報告書概要(欧文)」より
• [雑誌論文] Enhancement of osteogenesis on hydroxyapatite surface coated with synthetic pepride (EEEEEEEPRGDT)in vitro. (2002)
  • 著者名/発表者名: Itoh D, Yoneda S, Kuroda S, Kondo H, Umezawa A, Ohya K, Ohyama T, K asugai S.
  • 雑誌名: J Biomed Mater Res. 62 ページ: 292-298
  • 説明: 「研究成果報告書概要(和文)」より
  • 査読あり
• [雑誌論文] Analysis of human TIE2 function on hematopoietic stem cells in umbilical cord blood. (2002)
  • 著者名/発表者名: Yuasa H, Takakura N, Shimomura T, Suenobu S, Yamada T, Nagayama H, Oike Y, Suda T
  • 雑誌名: Biochem Biophys Res Commun. 298 ページ: 731-737
  • 説明: 「研究成果報告書概要(和文)」より
  • 査読あり
• [雑誌論文] Enhancement of osteogenesis on hydroxyapatite surface coated with synthetic peptide(EEEEEEEPRGDT)in vitro (2002)
  • 著者名/発表者名: Itoh D, Yoneda S, Kuroda S, Kondo H, Umezawa A, Ohya K, Ohyama T, Kasugai S.
  • 雑誌名: J Biomed Mater Res. 62(2) ページ: 292-298
  • 説明: 「研究成果報告書概要(欧文)」より
• [雑誌論文] 「研究成果報告書概要(欧文)」より (2002)
  • 著者名/発表者名: Yuasa H, Takakura N, Shimomura T, Suenobu S, Yamada T, Nagayama H, Oike Y, Suda T
  • 雑誌名: Biochem Biophys Res Commun 298(5) ページ: 731-737
• [雑誌論文] Brain from Bone : Efficient "meta-differentiation" of marrow stroma-derived mature osteoblasts to neurons with noggin ora demethylating agent. (2001)
  • 著者名/発表者名: Kohyama,J., Abe,H., Shimazaki,T., Koizumi,A., Nakashima,K., Gojo,S., Taga,T., Okano,H., Hata,J., Umezawa,A
  • 雑誌名: Differentiation 68 ページ: 235-244
  • 説明: 「研究成果報告書概要(和文)」より
  • 査読あり
• [雑誌論文] Brain from Bone : Efficient "meta-differentiation" of marrow stroma-derived mature osteoblasts to neurons with noggin ora demethylating agent (2001)
  • 著者名/発表者名: Kohyama, J., Abe, H., Shimazaki, T., Koizumi, A., Nakashima, K., Gojo, S., Taga, T., Okano, H., Hata, J., Umezawa, A.
  • 雑誌名: Differentiation 68 ページ: 235-244
  • 説明: 「研究成果報告書概要(欧文)」より
• [学会発表] Enhanced calcification and osteoblastic differentiation of human bone marrow stromal cells by Notch. (2002)
  • 著者名/発表者名: Hozumi N, Yasuda M, Morimura N, Watanabe N, Fujimaki R, Hata J, Yamada T, Tezuka K.
  • 学会等名: The 5th Tissue Engineering Society International
  • 発表場所: 神戸
  • 年月日: 2002-12-10
  • 説明: 「研究成果報告書概要(和文)」より
• [学会発表] Enhanced calcification and osteoblastic differentiation of human bone marrow stromal cells by Notch (2002)
  • 著者名/発表者名: Hozumi N, Yasuda M, Morimura N, Watanabe N, Fujimaki R, Hata J, Yamada T, Tezuka K.
  • 学会等名: The 5th Tissue Engineering Society International
  • 発表場所: Kobe, Japan
  • 説明: 「研究成果報告書概要(欧文)」より
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• [文献書誌] Yuasa, H., Takakura, N., Shimomura, T., Suenobu, S., Yamada, I.et al.: "Analysis of human TlE2 function on hematopoietic stem cells in umbilical cord blood"BBRC. 298. 731-737 (2002)
• [文献書誌] Nishimura, N., Nakayama, T., Tonoike, H., Yamada, T.et al.: "Various amplification of direct PCR using Blood Samples"Clinical Laboratory. 48. 377-384 (2002)
• [文献書誌] Kakimoto, I., Hattori, Y., Okamoto, S., Yamada, T.et al.: "Thalidomide for the Treatment of Refractory Multiple Myeloma: Association of Plasma Concentrations of Thalidomide and Angiogenic Growth Factors with Clinical Outcome"Jpn J Cancer Res. 93. 1029-1036 (2002)
• [文献書誌] Zhao, C., Hashiguchi, A., Kondoh, K., Du W., Hata, J., Yamada T.: "Exogenous expression of heat shock protein 90kDa retards the cell cycle and impairs the heat shock response"Experimental Cellular Research. 275. 200-214 (2002)
• [文献書誌] Sato, N., Hattori, Y., Du W., Yamada, T., Kamata, T.et al.: "Elevated level of basic fibroblast growth factor in multiple myeloma correlates with increased disease activity"Jpn J Cancer Res. 93. 459-466 (2002)
• [文献書誌] Yamaoka, T., Yoshida, K., Yamada, T., Yano, M., Matsui, T., Hata, J.et al.: "Transgenic expression of FGF8 and FGF10 induces transdifferntiation of panceratic islet cells into hepatocytes and exocrine cells"BBRC. 292. 138-143 (2002)
• [文献書誌] Fukao, T., Yamada, T., Tanabe, M., Terauchi, Y., Hata, J.et al.: "Selective loss of gastrointestinal mast cells and impaired immunity to intestinal parasites in Pik3r1 deficient mice"Nature Immunology. 3. 295-304 (2002)
• [文献書誌] Matsuoka, K., Kiyokawa, N., Taguchi, Fujimoto, J.et al.: "Rum1, an inhibitor of cyclin-dependant kenase in fission yeast is negatively by mitogen-activated protein kinase-mediated phosphorylation at Ser and Thr residues"Eur-J-Biochem. 269. 3511-3521 (2002)
• [文献書誌] Saito, M., Kiyokawa, N., Taguchi, T., Suzuki, K., Fujimoto, J.et al.: "Granulocyte Colony-stimulating Factor Directly Affects Human Monocytes and Modulates Cytokine Secretion"Exp-Hematol. 30. 1115-1123 (2002)
• [文献書誌] Katagiri-U Y., Ohmi, K., Tang, W., Takenouchi, H., Fujimoto, J.et al.: "Raft.1, a monoclonal antibody raised against the raft microdomain, recognizes G-protein b1 and 2, which assemble near nucleus after Shiga toxin binding to human renal cell line"Lab-Inv. 82. 1735-1745 (2002)
• [文献書誌] Nakao, H., Kataoka, C., Kiyokawa, N., Fujimoto, J., Yamasaki, S., Iakeda, T.: "Monoclonal antibody to shiga toxin 1,which blocks receptor binding and neutralizes cytotoxicity"Microbiol-Immunol. 777-780 (2002)
• [文献書誌] Taguchi, T., Kiyokawa, N., Mimori, K., Suzuki, T., Fujimoto, J.et al.: "Pre-BCR-mekiated signal inhibits CD24-induced apptosis in human pre-B cells"J-Immunol. 170. 252-260 (2003)
• [文献書誌] Mori, T., Kiyokawa, N., Shimada, H., Miyauchi, J., Fujimoto, J.: "Retrospective analysis of 34 patients diagnosed at the National Research Institute for Child Health and Development"Br-J-Haematol. (in press).
• [文献書誌] Ohtomo, Y., Kawamura, R., Kaneko, K., Yamashiro, Y., Fujimoto, J.et al.: "Nephrotic syndrome associated with human parvovirus B19 infection"Pediatr Nephrol A. (in press).
• [文献書誌] Mimori, K., Kiyokawa, N., Taguchi, T., Suzuki, T., Fujimoto, J.et al.: "Co-stimulatory signals distinctively affect CD20-and B-cell-antigen-receptor mediated apoptosis in Burkitt fs lymphoma/leukemia cells"Leukemia. (in press).
• [文献書誌] Hakuno, D., Fukuda, D., Makino, S., Konishi, F., Umezawa, A.et al.: "Bone marrow-derived regenerated cardiomyocytes (CMG cells) express functional adrenergic and muscarnic receptors"Circulation. 105. 380-386 (2002)
• [文献書誌] Ochi, K., Chen, G., Ushida, T., Gojo, S., Hata, J., Umezawa, A.et al.: "The use of osolate mature osteoblasts in abundance acts as desired-shaped bone regeneration in combination with a modified poly DL-lactic-co-glycokic acid (PLGA)-collagen sponge"J Cell Physiol. 194. 45-53 (2003)
• [文献書誌] Suzuki, S., Tanaka, K., Nogawa, S., Umezawa, A., Hata, J.et al.: "Expression of interleukin-6 in cerebral neurons and ovarian cancer tissue in Trousseau syndrome"Clin Neuropathol. 21(5). 232-235 (2002)
• [文献書誌] Inoshita, S., Takeda, K., Hatai, T., Hata, J., Umezawa, A.et al.: "Phosphorylation and Inactivation of Myeloid Cell Leukemia 1 by JNK in Response to Oxidative Stress"J Biological Chemistry. 277(46). 43730-43734 (2002)
• [文献書誌] Imabayashi, H., Mori, T., Gojo, S., Hata, J., Umezawa, A.et al.: "Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis"Exp Cell Res. (in press).
• [文献書誌] Matsushita, K., Okita, H., Suzuki, A., Hata, J., Umezawa, A.et al.: "Islet cell hyperplasia in transgenic mice overexpressing EAT/mcl-1, a bcl-2 related gene"Mol Cell Endocr. (in press).
• [文献書誌] Itoh, D., Yoneda, S., Kuroda, S., Kondo, H., Umezawa, A., Ohya, K.et al.: "Enhancement of osteogenes is on hydroxyapatite surface coated with synthetic peptide (EEEEEEEPRGDT) in vitro"J Biomed Mater Res. 62(2). 292-298 (2002)
• [文献書誌] Katagiri-U Y., Ohmi, K., Katagiri, C., Fujimoto, J., et al.: "Prominent inimunogenicity of monosialosyl galactosylgloboside, carrying a stage-specfic embryonic antigen-4(SSEA-4)-"Glycoconj-J. 18(4). 347-353 (2001)
• [文献書誌] Nakajima, H., Kiyokawa, N., Fujimoto, J.et al.: "Kinetic analysis of binding between Shiga toxin and receptor gly colipid Gb3Cerby surface plasmon resonance"J. Biol-Chem. 276(46). 42915-42922 (2001)
• [文献書誌] Ohmi, K., Kiyokawa, N., Sikino T., Fujimoto J.et al.: "Nitrobenzylthioinosine(NBT), a Nuoleoside Transport Inhibitor, Protects against ShigaToxin Cytotoxicity in Human Microvascular-"Endothelium (J. Endothol Cell Res). 8(4). 261-268 (2001)
• [文献書誌] Nakajima, H., Katagiri-U Y., Fujimoto, J.et al.: "Single step method for puritication of Shiga toxin 1 B subumit using receptor mediated affinity chromatography by -"Protein Expression and Purification. 22(2). 267-275 (2001)
• [文献書誌] Ebata, T., Mogi, S., Hata, Y., Fujimoto, J.et al.: "Rapid induction of CD95 ligand and CD4+T cell-mediated apoptosis by CD137(4-1BB) costimulation"Eur-J-lmmunol. 31. 1410-1416 (2001)
• [文献書誌] Fujita, T., Yamada, T., Hashiguchi, A., Fujimoto, J.et al.: "Augmentation of megakaryocytopoiesis by the hematopoietic micro environment human granulocyte colony-stimulating factor -"Exp Hematol. 29. 1010-1018 (2001)
• [文献書誌] Suzuki, T., Kiyokawa, N., Taguchi, T., Fujimoto, J.et al.: "CD24 induces apoptosis in human B cells via the GEM/rafts mediatd signaling system"J-Immunol. 166(9). 5567-5577 (2001)
• [文献書誌] Katagiri-U Y., Kiyokawa, N., Fujimoto, J.: "The effect of Shiga Toxin binding to globotriaosyiceramide in rafts of human kidney cells and Burkitt's lymphoma Ramos cells"Trends-Glycosci-Glyc. 13. 281-290 (2001)
• [文献書誌] Kiyokawa, N., Mori, T., Taguchi, T., Fujimoto, J.et al.: "Activation of the caspase cascade during Stxi-induced apoptosis in Burkitt's lymphoma cells"J-Cell-Biochem. 81(1). 128-142 (2001)
• [文献書誌] Katagiri-U Y., Kiyokawa, N., Fujimoto, J.: "A role for lipid rafts in immune cell signaling. (review)"Microbiol-lmmunol. 45(1). 1-8 (2001)
• [文献書誌] Sato, N., KiyoKawa, N., Takada, K., Fujimoto, J.et al.: "Characterization, of monoclonal antibodies against mouse and rat platelet glycoprotein V(CD42d)"Hybridoma. 19(6). 455-461 (2000)
• [文献書誌] Fukuchi, T., Umezawa, A., Hata, J., et al.: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differntiation of CML cells"Oncogene. 20. 704-713 (2001)
• [文献書誌] Ochi, K., Nozaki, H., Hata, J., Umezawa, A.et al.: "Specific bisulfite modification of CTG triiplet repeats of the androgen receptor gene, a gene associated with the triplet-"Neuroscience Research Communications. 28(1). 1-10 (2001)
• [文献書誌] Hamatani, T., Sasaki, H., Hata, J., Umezawa, A.et al.: "Epigenetic mark sequence of the H19 gene in human sperm"Biochim Biophys Acta. 1518(1-2). 137-144 (2001)
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• [文献書誌] Shinoda, K., Yamada, T., Umezawa, A., Hata, J.et al.: "Light-induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apototic bcl-2-related-"Br J Ophthalmol. 85. 1237-1243 (2001)
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• [文献書誌] Muto, A., Kizaki, M., Umezawa, A., Hata.J.et al.: "A novel differntiation-indUcing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF"Leukemia. 15(8). 1176-1184 (2001)
• [文献書誌] Kohyama, J., Abe, H., Hata, J., Umezawa, A.et al.: "Brain from Bone : Efficient "meta-differntiation" of marrow stroma derived mature osteoblasts to neurons with noggin or a -"differentiation(Special issue on stem cells). 68. 235-244 (2001)
• [文献書誌] Hakuno, D., Fukuda, D., Makino, S., Umezawa, A.et al.: "Bone marrow-derived regenerated cardiomyocytes(CMG cells) express functional adrenergic and muscarinic receptors"Circulation. 105. 380-386 (2002)
• [文献書誌] Ohyama, M., Amagal, M., Hata, J., Umezawa, A.et al.: "Immunologic and histoopathologic characterization of active disease model mouse for pemphigus vulgaris"J Invest Dermatol. (in press).
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